Pyrimidineamine derivatives and processes for the preparation thereof

ABSTRACT

N-phenyl-2-pyrimidineamine derivatives of formula (I) wherein the substituents are as defined in claim 1 are described. Those compounds can be used for example, in the treatment of tumour diseases. ##STR1##

This is a 371 of PCT/EP 94/03150, filed Sep. 21, 1994.

The invention relates to N-phenyl-2-pyrimidineamine derivatives, toprocesses for the preparation thereof, to medicaments comprising thosecompounds, and to the use thereof in the preparation of pharmaceuticalcompositions for the therapeutic treatment of warm-blooded animals.

The invention rehtes to N-phenyl-2-pyrimidineamine derivatives offormula I ##STR2## wherein R₁ is naphthyl, fiuorenyl, anthracenyl or asubstituted cyclic radical, the cyclic radical being bonded to a ringcarbon atom in each case and being selected from phenyl, pyridyl,1H-indolyl, pyrazinyl, thiazolyl, pyrimidinyl, pyridazinyl andimidazolyl, and the substituents of the above-mentioned phenyl radicalbeing selected from hydroxy, halogen, nitro, cyano, unsubstituted orhalogen-substituted lower alkoxy, from a radical of formula II

    --C(═O)--(O).sub.m --R.sub.3                           (II)

wherein

m is 0 or 1 and

R₃ is hydrogen, benzyl, lower alkyl or amino-lower alkyl wherein theamino group is free, lower alkylated or lower alkanoylated, from aradical of formula III

    --C(═O)--N(R.sub.4)R.sub.5                             (III)

wherein

R₄ and R₅ are each independently of the other hydrogen or unsubstitutedor amino- or hydroxy-substituted lower alkyl, from a radical of formulaIV

    --SO.sub.2 --N(R.sub.6)R.sub.7                             (IV)

wherein

R₆ and R₇ are each independently of the other hydrogen, lower alkyl oramino-lower alkyl, or wherein

R₆ and R₇ together form the bivalent radical --(CH₂)₂ --NH--(CH₂)₂ 13 ,and from a radical of formula V

    --N(R.sub.8)R.sub.9                                        (V)

wherein

R₈ and R₉ are each independently of the other lower alkyl, or wherein

R₈ is hydrogen and

R₉ is amino or amino-cyclohexyl, or is lower alkyl that is substitutedby imidazolyl, guanidyl, lower alkylamino-carbonylamino, amidino,di-lower alkylamino-cyclohexyl, piperazinyl, carboxy, loweralkoxycarbonyl, carbamoyl, N-hydroxy-carbamoyl, hydroxy, lower alkoxy,dihydroxyphosphoryloxy or by formylpiperazinyl, and the substituents ofthe other above-mentioned cyclic radicals being selected from hydroxy,halogen, cyano, amino-lower alkyl, unsubstituted or halogen-substitutedlower alkoxy, phthalimido-substituted lower alkyl, from a radical of theabove-mentioned formulae II, III or IV and from a radical of formula VI

    --N(R.sub.10)R.sub.11                                      (VI)

wherein

R₁₀ and R₁₁ are each independently of the other hydrogen or lower alkyl,or wherein

R₁₀ is hydrogen and

R₁₁ is amino or amino-cyclohexyl, or is lower alkyl substituted byamino, lower alkylamino, di-lower alkylamino, lower alkanoylamino,imidazolyl, guanidyl, lower alkyl-amino-carbonylamino, amidino, di-loweralkylamino-cyclohexyl, piperazinyl, formylpiperazinyl, carboxy, loweralkoxycarbonyl, carbamoyl, N-hydroxy-carbamoyl, hydroxy, lower alkoxy,dihydroxyphosphoryloxy or by glycylamido; and

R₂ is nitro, fluorine-substituted lower alkoxy or a radical of formulaVII

    --N(R.sub.12)--C(═X)--(Y).sub.n --R.sub.13             (VII)

wherein

R₁₂ is hydrogen or lower alkyl,

X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-loweralkyl-hydroximino,

Y is oxygen or the group NH,

n is 0 or 1, and

R₁₃ is an aliphatic radical having at least 5 carbon atoms, or anaromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,heterocyclic or heterocyclic-aliphatic radical,

and to salts of such compounds having at least one salt-forming group.

Naphthyl R₁ is 1-naphthyl or 2-naphthyl.

Anthracenyl R₁ is preferably 9-anthracenyl.

Fluorenyl R₁ is preferably 2-fluorenyl.

A substituted phenyl radical R₁ can have several substituents, butespecially not more than 3 and, especially in the case of relativelylarge substituents, preferably only one substituent, which substituentsare principally in the para- (or 4-position) anct/or preferablymeta-position (or 3-position). The other above-mentioned substitutedcyclic radicals R₁ generally have up to two and preferably only onesubstituent, which is especially in the rneta- or para-position withrespect to the bonding site of the cyclic radical R₁.

Pyridyl bonded to a ring carbon atom is 2- or preferably 4- or3-pyridyl, especially 4-pyridyl. In a mono-substituted pyridyt radicalR₁, the substituent is preferably in the ortho-position with respect tothe pyridine nitrogen.

1H-indolyl bonded to a carbon atom of the five-membered ring is1H-indol-2-yl or preferably 1H-indol-3-yl. In mono-substituted1H-indolyl, the substituent is preferably in the 1-position, that is tosay, at the nitrogen.

Halogen in a radical R₁ is preferably chlorine or fluorine.

Halogen-substituted phenyl R₁ is preferably 2-, 3- or 4-chloro-phenyl,2,4-, 3,4- or 2,5- dichloro-phenyl or 2,3,4-trichloro-phenyl

Unsubstituted or halogen-substituted lower alkoxy as substituent of asubstituted phenyl radical R1 is preferably methoxy, ethoxy ortrifiuoro-methoxy.

A radical of formula II is, for example, a radical wherein m is 1 and R₃is hydrogen, that is to say, carboxy.

A radical of formula III is, for example, a radical wherein R₄ ishydrogen and R₅ is hydrogen, ω-amino-alkyl having 2 or 3 carbon atoms orω-hydroxy-alkyl having 2 or 3 carbon atoms, that is to say, carbamoyl,2-amino-ethyl, 2-hydroxy-ethyl, 3-amino-propyl or 3-hydroxy-propyl

A radical of formula IV is, for example, a radical wherein R₆ ishydrogen and R₇ is ω-amino-C₂₋₃ alkyl or wherein R₆ and R₇ together formthe bivalent radical --(CH₂)₂ --NH--(CH₂)₂ --, that is to say, they forma piperazinyl ring together with the nitrogen atom to which R₆ and R₇are bonded.

Amino-cyclohexyl R₉ or R₁₁ is preferably 4-amino-cyclohexyl. Di-loweralkylaminocyclohexyl as the radical R₉ or as part of a substituted loweralkyl radical R₉ or R₁₁ is preferably 4-di-lower alkylamino-cyclohexyl,preferably 4-dimethylamino-cyclohexyl.

Lower alkylamino in a radical R₉ or R₁₁ is preferably methylamino.

Di-lower alkylamino in a radical R₉ or R₁₁ is preferably dimethylamino.

Lower alkanoylamino in a radical R₉ or R₁₁ is preferably acetylamino.

Formyl-piperazinyl in a radical R₉ or R₁₁ is preferably4-formyl-piperazinyl.

Lower alkyl R₉ substituted by imidazolyl, guanidyl, loweralkylamino-carbonylamino, amidino, di-lower alkylamino-cyclohexyl,piperazinyl, carboxy, lower alkoxycarbonyl, carbamoyl,N-hydroxy-carbamoyl, hydroxy, lower alkoxy, dihydroxyphosphoryloxy or byformylpiperazinyl, or lower alkyl R₁₁ substituted by amino, loweralkylamino, di-lower alkylamino, lower alkanoylamino, imidazolyl,guanidyl, lower alkylamino-carbonylamino, amidino, di-loweralkylamino-cyclonexyl, piperazinyl, formylpiperazinyl, carboxy, loweralkoxycarbonyl, carbamoyl, N-hydroxy-carbamoyl, lower alkoxy,dihydroxyphosphoryloxy or by glycylamido is preferably toorio-, di- ortri-methylene substituted in that manner, the substituents preferablybeing in the ω-position. In addition, hydroxy-substituted lower alkyl R₉or R₁₁ is preferably also 2-hydroxy-propyl.

Fluorine-substituted lower alkoxy R₂ is lower alkoxy that carries atleast one, but preferably several, fluorine substituents, especiallytrifluoromethoxy or more especially 1,1,2,2-tetrafluoro-ethoxy.

When X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-loweralkyl-hydroximino, the group C═X is, in the order mentioned, the radicalC═O, C═S, C═N--H, C═N-lower alkyl, C═N--OH or C═N--O -lower alkyl. X ispreferably oxo.

n is preferably 0, that is to say, the group Y is not present.

Y, if present, is preferably the group NH.

Within the scope of this text, the term "lower" denotes radicals havingup to and including 7, preferably up to and including 4, carbon atoms.

Unless otherwise indicated in the context concerned, lower alkyl ispreferably methyl or ethyl.

An aliphatic radical R13 having at least 5 carbon atoms preferably hasnot more than 22 carbon atoms and generally not more than 10 carbonatoms and is such a substituted or preferably unsubstituted aliphatichydrocarbon radical, that is to say, such a substituted or preferablyunsubstituted alkynyl, alkenyl or preferably alkyl radical, such as C₅-C₇ alkyl, for example n-pentyl. An aromatic radical R₁₃ has up to 20carbon atoms and is unsubstituted or substituted, for example naphthyl,such as especially 2-naphthyl, or preferably phenyl, each of which isunsubstituted or substituted, the substituents preferably being selectedfrom cyano, lower alkyl that is unsubstituted or substituted by hydroxy,amino or by 4-methyl-piperazinyl, such as especially methyl, fromtrifluoromethyl, free, etherified or esterified hydroxy, free, alkylatedor acylated amino and from free or esterified carboxy. In anaromatic-aliphatic radical R₁₃, the aromatic moiety is as defined aboveand the aliphatic moiety is preferably lower alkyl, such as especiallyC₁ -C₂ alkyl, that is substituted or preferably unsubsfituted, forexample benzyl. A cycloaliphafic radical R₁₃ has especially up to 30,principally up to 20 and more especially up to 10 carbon atoms, is mono-or poly-cyclic and is substituted or preferably unsubstituted, forexample such a cycloalkyl radical, especially a 5- or 6-memberedcycloalkyl radical, such as preferably cyclohexyl. In acycloaliphafic-aliphafic radical R₁₃, the cycloaliphatic moiety is asdefined above and the aliphatic moiety is preferably lower alkyl, suchas especially C₁ -C₂ -alkyl that is substituted or preferablytinsubstituted. A heterocyclic radical R₁₃ contains especially up to 20carbon atoms and is preferably a saturated or unsaturated monocyclicradical having 5 or 6 ring members and from 1 to 3 hetero atoms whichare preferably selected from nitrogen, oxygen and sulfur, especially,for example, thienyl or 2-, 3- or 4-pyridyl, or a bi- or tri-cyclicradical, wherein, for example, one or two benzene radicals are fused(annellated) to the mentioned monocyclic radical. In aheterocyclic-aliphatic radical R₁₃, the heterocyclic moiety is asdefined above and the aliphatic moiety is preferably lower alkyl, suchas especially C₁ -C₂ alkyl, that is substituted or preferablyunsubstituted.

Etherified hydroxy in a radical R₁₃ is preferably lower alkoxy.Esterified hydroxy in a radical R₁₃ is preferably hydroxy esterflied byan organic carboxylie acid, such as a lower alkanoic acid, or by amineral acid, such as a hydrohalic acid, for example lower alkanoyloxyor especially halogen, such as iodine, bromine or especially fluorine orchlorine.

Alkylated amino in a radical R₁₃ is, for example, lower alkylamino, suchas methylamino, or di-lower alkylamino, such as dimethylamino. Acylatedamino is, for example, lower alkanoylamino or benzoylamino.

Esterified carboxy in a radical R₁₃ is, for example, loweralkoxycarbonyl, such as methoxycarbonyl.

Salt-forming groups in a compound of formula I are groups or radicalshaving basic or acidic properties. Compounds having at least one basicgroup or at least one basic radical, for example a free amirto group, apyrazinyl radical or a pyridyl radical, can form acid addition salts,for example with inorganic acids, such as hydrochloric acid, sulfuricacid or a phosphoric acid, or with suitable organic carboxylic orsurfonic acids, for example aliphatic mono- or di-carboxylic acids, suchas trifiuoroacetic acid, acetic acid, propionic acid, glycolic acid,succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malicacid, tartaric acid, citric acid, oxalic acid or amino acids, such asarginine or lysine, aromatic carboxylic acids, such as benzoic acid,2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid,4-aminosalicylic acid, aromatic-aliphatic carboxylic acids, such asmandelic acid or cinanmic acid, heteroaromatic carboxylic acids, such asnicotinic acid or isonicotinic acid, aliphatic sulfonic acids, such asmethane-, ethane- or 2-hydroxyethane-sulfonic acid, or aromatic sulfonicacids, for example benzene-, p-oluene- or naphthalene-2-sulfonic acid.If several basic groups are present, mono- or poly-acid addition saltscan be formed.

Compounds of formula I having acidic groups, for example a free carboxygroup in the radical R₁, can form metal or ammonium salts, such asalkali metal or alkaline earth metal salts, for example sodium,potassium, magnesium or calcium salts, or ammonium salts with ammonia orsuitable organic amines, such as tertiary monoamines, for exampletriethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, forexample N-ethyl-piperidine or N,N'-dimethyl-piperazine.

Compounds of formula I that possess both acidic and basic groups canform internal salts.

For the purpose of isolation or purification and also in the case of thecompounds used further as intermediates, it is also possible to usepharmaceutically unacceptable salts. Only the pharmaceuticallyacceptable non-toxic salts are used therapeutically, however, and thoseare therefore preferred.

In view of the close relationship between the novel compounds in freeform and in the form of their salts, including also salts that can beused as intermediates, for example in the pitcation of the novelcompounds or in order to identify those compounds, hereinbefore andhereinafter any reference to the free compounds is to be understood asincluding also the corresponding salts, where appropriate and expedient.

The compounds of formula I exhibit valuable pharmacological properties:for example, they inhibit the enzyme protein kinase C with a high degreeof selectivity. Phospholipid- and calcium-dependent protein kinase Coccurs in cells in a number of forms and participates in variousfundamental processes, such as signal transmission, proliferation anddifferentiation, and also the release of hormones and neurotransmitters.The activation of that enzyme is effected either by receptor-mediatedhydrolysis of phospholipids of the cell membrane or by directinteraction with certain tumour-promoting active substances. Thesensitivity of the cell to receptor-mediated signal transmission can besubstantially influenced by modifying the activity of protein kinase C(as a signal transmitter).

Compounds that are capable of influencing the activity of protein kinaseC can be used as tumour-inhibiting, antiinflammatory, immunomodulatingand antibacterial active ingredients and may even be of value as agentsagainst atherosclerosis and disorders of the cardiovascular system andcentral nervous system.

Formerly, porcine brain protein kinase C purified in accordance with theprocedure described by T. Uchida and C. R. Filburn in J. Biol. Chem.259, 12311-4 (1984) was used to determine the inhibitory action onprotein kinate C, and the inhibitory action on protein kinase C wasdetermined in accordance with the procedure of D. Fabbro et al., Arch.Biochem. Biophys. 239, 102-111 (1985).

The porcine brain protein kinase C formerly used is a mixture of varioussub-types (isotypes) of protein kinase C. If pure recombinant isotypesare used instead of porcine brain protein kinase C in the above test itis found that the compounds of formula I inhibit the "conventional"isotype α preferentially whereas the other "conventional" isotypes β-1,β-2 and γ and especially the "non-conventional" isotypes δ, ε and η andthe "atypical" isoform ζ are inhibited to a distinctly lesser extent andin some cases hardly at all

Recombinant PKC isotypes are cloned, expressed and purified in thefollowing manner:.

The production of various proteins with the aid of baculoviruses, andtheir cloning and isolation from Sf9 insect cells are carried out asdescribed by M. D. Summers and G. E. Smith, "A manual method forbaculovirus vectors and insect cell culture procedure", Texas Agricul.Exptl. Station Bull. (1987), 1555. The construction and isolation ofrecombinant viruses for the expression of PKC-α (bovine), PKC-β1(human), PKC-β2 (human) and PKC-γ (human/bovine hybrid) in Sf9 cells areeffected in the manner described by Stabel et al. [S. Stabel, M.Liyanage and D. Frith, "Expression of protein kinase C isozymes ininsect cells and isolation of recombinant proteins", Meth. Neurosc.(1993)]. The production of the PKC isotypes in Sf9 cells is carried outin the manner indicated by Stabel et al. (see above), and thepurification of the enzymes is effected in accordance with the methoddescribed in the publication by MeGlynn et al. [E. MeGlynn, J.Liebetanz, S. Reutener, J. Wood, N. B. Lydon, H. Hofstetter, M. Vanek,T. Meyer and D. Fabbro, "Expression and partial characterization of ratprotein kine C-δ and protein kinase C-ζ in insect cells usingrecombinant baculovirus", J. Cell. Biochem. 49, 239-250 (1992)]. For thegeneration of recombinant PKC-δ (rat), PKC-ε (rat), PKC-ζ (rat) andPKC-η (mouse), and their expression and pitcation, the proceduredescribed by Liyanage et al. ["Protein kinase C group B members PKC-δ,-ε, -ζ and PKC-λ: Comparison of properties of recombinant proteins invitro and in vivo", Biochem. J. 283, 781-787 (1992)] and McGlynn et al.,respectively, (see above) is followed, with the additional feature thatthe transfer vector pAc360 is used for the expression of PKC-η [V.Luckow and M.D. Summers, "Trends in the development of baculovirusexpression", Biotechnology 6, 47-55 (1988)].

The measurement of the activity of the recombinant PKC isotypes obtainedby the above method is carried out in the absence of lipid and calcium(co-factors). Protamine sulfate phosphorylated in the absence ofco-factors is used as the substrate. The activity of the enzymesreflects the transfer of ³² P from γ-[³² P]-ATP to protamine sulfate.Protamine sulfate is a mixture of polypeptides each comprising fourC-terminal arginine residues. Phosphate incorporation is measured underthe following conditions: 100 μl of the reaction mixture comprise infinal concentrations 20 mM TRIS-HCl pH 7.4, 10 mM Mg[NO₃ ]₂, 0.5 mg/mlof protamine sulfate, 10 μM ATP (0.1 μCi γ-[³² P]-ATP; 10 Ci/mol;Amersham, Little Chalfont, United Kingdom), various concentrations ofthe inhibitory compounds and 0.5-2.5 U (units: a unit is the amount ofenzyme that, in one minute and per milligram of protein, transfers onenanomole of ³² P from the above-mentioned γ-[³² P]-ATP to historne H1[Sigma, type V-S]) of the enzymes. The reaction is started by theaddition of the enzymes and transfer at 32° C. The reaction time is 20minutes. The reaction is then stopped by dripping aliquots of 50 μl ontoP81 chromatography paper (Whatman, Maidstone, United Kingdom). Afterremoving unbound γ-[³² P]-ATP and nucleotide fragments by washingoperations as described by J. J. Witt and R. Roskoski, "Rapid proteinkinase assay using phospho-cellulose-paper absorption", Anal. Biochem.66, 253-258 (1975), the substrate phosphorylation is determined byscintillation measurement. In that test, the compounds of formula Iinhibit the α-isotype of protein kinase C (PKC) at an IC₅₀ of as low asapproximately from 0.1 to 5.0 μmol/litre, generally approximately from0.1 to 1.0 μmol/litre. In contrast, the other isotypes of PKC aregenerally inhibited only at distinctly higher concentrations (i.e. atconcentrations up to more than 300 times higher).

As may be expected purely on the basis of the above-described inhibitoryaction on protein kinase C, the compounds of formula I exhibitantiproliferative properties which can be demonstrated directly inanother test described in the following in which the inhibitory actionof the compounds of formula I on the growth of human T24 bladdercarcinoma cells is determined. Those cells are incubated in Eagle'sminimal essential medium, to which 5% (v/v) foetal calf serum has beenadded, in a humidified incubator at 37° C. and with 5% by volume of CO₂in the air. The carcinoma cells (1000-1500) are sown in 96-wellmicrotitre plates and incubated overnight under the above-mentionedconditions. The test compound is added in serial dilutions on day 1. Theplates are incubated for 5 days under the above-mentioned conditions.During that period the control cultures undergo at least four celldivisions. After incubation, the cells are fixed with 3.3% (w/v) aqueonsglutaraldehyde solution, washed With water and stained with 0.05%(weight/volume) aqueous methylene blue solution. After washing, the dyeis eluted with 3% (w/v) aqueous hydrochloric acid. The optical density(OD) per well, which is directly proportional to the number of cells, isthen measured at 665 nan using a photometer CTitertek multislam). TheIC₅₀ values are calculated with a computer system using the formula##EQU1##

The IC₅₀ values are defined as being the concentration of activeingredient at which the number of cells per well at the end of theincubation period is only 50% of the number of cells in the controlcultures. In the case of the compounds of formula I, the IC₅₀ values soascertained are approximately from 0.1 to 10 μmol/litre.

The anti-tumour activity of the compounds of formula I can also bedemonstrated in vivo:

Female Balb/c hairless mice with s.c. transplanted human bladder tumoursT24 are used to determine the anti-tumour activity. On day 0, with theanimals under peroral forene narcosis, approximately 25 mg of a solidturnour are placed under the skin on the animals' left flank and thesmall incised wound is closed by means of suture clips. On day 6 afterthe transplantation, the mice are divided at random into groups of 6animals and treatment commences. The treatment is carried out for 15days with peroral or intraperitoneal administration once daily of acompound of formula I in dimethyl sulfoxiderrween 80/-sodium chloridesolution in the various doses. The turnouts are measured twice a weekwith a slide gauge and the volume of the tumours is calculated. In thattest, the peroral or intraperitoneal administration of a compound offormula I brings about a marked reduction in the average tumour volumein comparison with the untreated control animals.

On the basis of the properties described, the compounds of formula I canbe used especially as tumour-inhibiting active ingredients, for examplein the treatment of tumours of the bladder and the skin. When thecompounds of formula I are used in the treatment of cancer incombination with other chemotherapeutic drugs, they prevent thedevelopment of resistance (multidrug resistance) or eliminate an alreadyexisting resistance to the other chemotherapeutic drugs. They are alsosuitable for the other uses mentioned above for protein kinase Cmodulators and can be used especially in the treatment of disordersresponsive to inhibition of protein kinase C.

Some of the compounds of formula I also inhibit the tyrosine kinaseactivity of the receptor for the epidermal growth factor (EGF). Thatreceptor-specific enzyme activity plays a key role in signaltransmission in a large number of mammalian cells, including humanceils, especially epithelial cells, cells of the immune system and cellsof the central and peripheral nervous system. in the case of varioustypes of cell, the EGF-induced activation of the receptor-associatedtyrosine protein kinase (EGF-R-TPK) is a pre-requisite for cell divisionand accordingly for the proliferation of a cell population. The additionof EGF-receptor-specific tyrosine kinase inhibitors thus inhibits thereplication of those cells.

Inhibition of EGF-receptor-specific tyrosine protein kinase (EGF-R-TPK)can be demonstrated, for example, using the method of E. McGlynn et al.,Europ. J. Biochem. 207, 265-275 (1992). The compounds according to theinvention inhibit the enzyme activity by 50% (IC50) for example at aconcentration of from 0.1 to 10 μM.

The compounds of formula I that inhibit the tyrosine kinase activity ofthe receptor for the epidermal growth factor (EGF) can accordingly beused, for example, in the treatment of benign or malignant tumottrs.They are able to bring about turmour regression and to preventmetastatic spread and the growth of micrometastases. They can be usedespecially in the case of epidermal hyperproliferation (psoriasis), inthe treatment of neoplasia of epithelial character, for examplemastocarcinoma, and in the case of leukaemia. The compounds can also beused in the treatment of disorders of the immune system and inflammationif protein kinases are involved. Furthermore, those compounds of formulaI can be used in the treatment of disorders of the central or peripheralnervous system if signal transmission by protein kinases is involved.

The compounds of formula I and salts of such compounds having at leastone salt-forming group also inhibit the enzyme p34^(cdc2) /cyclineB^(cdcx13) kinuse. That kinuse controls, in addition to othercdc2-related kinasea, specific phases of cell division, especially thetransition from the G₁ -phase to the S-phase and more especially thetransition from the G₂ -phase to the M-phase.

In chronological order, the cycle of a eukaryofic cell consists of theinterphase and the M-phase. The interphase is accompanied by an increasein the size of the cell. In chronological order, the interphase consistsfor its part of the G₁ -phase, the S-phase and the G₂ -phase. In the G₁-phase (G=gap) biosynthetic processes take place in the cell. In theS-phase (synthesis phase) the DNA doubles. The cell then enters the G₂-phase which ends with the commencement of mitosis.

In chronological order, the M-phase for its part consists of thedivision of the cell nucleus (mitosis) and the division of the cyWplasm(cytokinesis).

The above-mentioned inhibition of the enzyme p34^(cdc2) /cyclineB^(cdc13) kinuse can be demonstrated by the following test:

10 μM 1-methyl-aden;me are used to induce starfish oocytes to enter theM-phase. The oocytes are then frozen in liquid nitrogen and stored at-80° C. If necessary, the oocytes are homogenised and centrifuged, asdescribed in D. Arion et al., Cell 55, 371-378 (1988) and V. Rialet andL. Meijer, Anticancer Res. 11, 1581-1590 (1991). In order to purify thep34^(cdc2) /cycline B^(cdc13) kinuse, the supernatant of the oocytes isadded to p9^(CKSbs) -Sepharose grains prepared from recombinant humanprotein p9^(CKShs), as described in L. Azzi et al., Eur. J. Biochem.203, 353-360 (1992). After 30 minutes at 4° C. while being turnedconstantly, the grains are washed thoroughly and the active p34^(cdc2)/cycline B^(cdc13) kinuse is eluted with free protein p9^(CKShs) (3mg/ml). The eluted kinase is tested using historic H1 as substrate, asdescribed in L. Meijer et al., EMBO J. 8, 2275-2282 (1989) and EMBO J.10, 1545-1554 (1991). In that test, the compounds of formula I and saltsof such compounds having at least one salt-forming group exhibit aninhibiting concentration IC₅₀ [μmol/litre] of approximately from 0.1 to5, generally approximately from 0.2 to 2.

That finding would also lead to the expectation that the compounds offormula I and salts of such compounds having at least one salt-forminggroup can be used in the treatment of hyperproliferative disorders, suchas turnours and psoriasis.

The compounds of formula I also inhibit the production of HIV viruses,as shown by the test below, and can accordingly be used as agentsagainst the immune deficiency disease AIDS. The initial symptomsobserved after HIV infection in humans is foilowed by a clinical latencyperiod which can last several years. After that period, the stage knownas AIDS occurs and usually progresses to death. The latency period isattributed to several factors: immune response, occlusion of the virusesin lymph nodes or other tissue and entry into a stage of molecular andvital latency in which the infected cells do not complete the viral cellcycle, which is why infectious viruses cannot be produced and theinfection cannot spread. That stage of molecular latency has beeninvestigated using cell models, such as the ACH-2 cell line [K. Clouseet al., J. Immunol 142, 431 (1989)] and the U1 cell line [T. Folks etal., J. Immunol. 140, 117 (1988)]. Those cells are infected with HIV-1viruses, but have only a low content of infectious viruses. If, however,those cells are stimulated with physiologically relevant factors thatare known to be increased in AIDS patients, such as turnour necrosisfactor, interleukin-6 etc., or with chemical inductors, such as phorboldiesters, for example 13-O-acetyl-12-O-n-tetradecanoyl-phorbol, amassive production of virus follows. The ACH-2 and U1 cells arerepresentatives of two different cell families that are targets for HIVinfection, namely lymphocytes and macrophages.

Hitherto, effective prevention of the progression of HIV infection tothe outbreak of AIDS has not been possible. Many attempts have been madeto prevent virus replication after the outbreak of AIDS, that is to say,in a stage in which viruses are produced on a massive scale. Incontrast, the compounds of formula I interfere with cell processes thatlead to the activation of latently infected HIV cells without impairingnorma/cell processes, such as cell division.

If the above-mentioned U1 or ACH-2 cells are used as a model forvirallatency, it can be demonstrated that HIV virus production inducedby 13-O-acetyl-12-O-n-tetradeeanoylphorbol or tumour necrosisfactor-alpha are effectively inhibited by the compounds of formula I ata concentration of approximately from 0.001 to 1 μmol/litre, for exampleat 0.03 μmol/litre.

A preferred group comprises compounds of formula I wherein thesubstituted cyclic radical R_(l) is selected from phenyl, pyridyl and1H-indolyl, the phenyl substituents being selected from unsubstituted orfluorine-substituted lower alkoxy, from halogen, nitro, from a radicalof formula II wherein

m is 1 and

R₃ is hydrogen,

and from a radical of formula III wherein

R₄ is hydrogen and

R₅ is hydrogen or amino- or hydroxy-substimted lower alkyl,

and the substituents of the other above-mentioned cyclic radicals beingselected from hydroxy, halogen, lower alkoxy, from amino- orphthalimido-substituted lower alkyl, from a radical of formula IIwherein

m is 1 and

R₃ is hydrogen,

from a radical of formula III wherein

R₄ is hydrogen and

R₅ is hydrogen or amino- or hydroxy-substituted lower alkyl,

and from a radical of formula VI wherein

R₁₀ is hydrogen and

R₁₁ is amino or amino-cyclohexyl, or is lower alkyl substituted byamino, di-lower alkylamino, lower alkanoylamino, imidazolyl, guanidyl,lower alkylamino-carbonylamino, amidino, di-lower alkylamino-cyclohexyl,piperazinyl, formyl-piperazinyl or by glycylamido; and

R₂ is fluorine-substituted lower alkoxy or a radical of formuh VIIwherein

R₁₂ is hydrogen,

X is oxo, n is 0 and

R₁₃ is phenyl,

and salts of such compounds having at least one salt-forming group.

Especially preferred are compounds of formula I wherein R₁ is naphthyl,9-anthracenyl, 2-fiuorenyl or a substituted cyclic radical selected fromphenyl, pyridyl and 1H-indolyl, the phenyl substituents being selectedfrom C₁₋₂ alkoxy, chlorine, trifluoromethoxy, from a radical of formulaII wherein

m is 1 and

R₃ is hydrogen,

from a radical of formula III wherein

R₄ is hydrogen and

R₅ is hydrogen or C₂₋₃ alkyl substituted in the ω-position by amino orby hydroxy,

from a radical of formula IV wherein

R₆ is hydrogen and

R₇ is 2-amino-ethyl, or

R₆ and R₇ together form the bivalent radical --(CH₂)₂ --NH--(CH₂)₂ --,

and from a radical of formula V wherein

R₈ is hydrogen and

R₉ is C₂₋₃ alkyl substituted in the ω-position by amino, the pyridylsubstituents being selected from hydroxy, chlorine, methoxy, from aradical of formula II wherein

m is 1 and

R₃ is hydrogen,

from a radical of formula Ill wherein

R₄ is hydrogen and

R₅ is hydrogen or C₂₋₃ alkyl substituted in the ω-position by amino orby hydroxy,

from a radical of formula IV wherein

R₆ is hydrogen and

R₇ is 2-amino-ethyl, or

R₆ and R₇ together form the bivalent radical --(CH₂)₂ --NH--(CH₂)₂ --,

and from a radical of formula VI wherein

R₁₀ is hydrogen and

R₁₁ is hydrogen, C₁₋₄ alkyl, amino, 4-amino-cyclohexyl or2-hydroxy-propyl, or is C₁₋₄ -alkyl substituted in the ω-position byamino, dimethylamino, acetylamino, imidazol-1-yl, guanidyl,methylamino-carbonylamino, amidino, 4-dimethylamino-cyclohexyl,piperazin-1-yl, 4-formyl-piperazin-1-yl, carboxy, ethoxycarbonyl,carbamoyl, N-hydroxycarbamoyl, hydroxy, methoxy, dihydroxyphosphoryloxyor by glycylamido, and the 1H-indolyl substituents being selected fromC₂₋₃ alkyl substituted in the ω-position by amino or by phthalimido; and

R₂ is 1,1,2,2-tetrafluoro-ethoxy or a radical of formula VII wherein

R₁₂ is hydrogen,

X is oxo,

n is 0 and

R₁₃ is phenyl,

and salts of such compounds having at least one salt-forming group.

Especially preferred are particularly compounds of formula I wherein

R₁ is a substituted cyclic radical selected from phenyl, pyridyl and1H-indolyl, the phenyl substituents being selected from C₁₋₂ alkoxy,chlorine, trifluoromethoxy, from a radical of formula II wherein

m is 1 and

R₃ is hydrogen,

and from a radical of formula III wherein

R₄ is hydrogen and

R₅ is hydrogen or C₂₋₃ alkyl substituted in the ω-position by amino orby hydroxy,

the pyridyl substituents being selected from hydroxy, chlorine, methoxy,from a radical of formula II wherein

m is 1 and

R₃ is hydrogen,

from a radical of formula III wherein

R₄ is hydrogen and

R₅ is hydrogen or C₂₋₃ aalkyl substituted in the ω-position by amino orby hydroxy,

and from a radical of formula VI wherein

R₁₀ is hydrogen and

R₁₁ is amino or 4-amino-cyclohexyl, or is C₁₋₄ alkyl substituted in theω-position by amino, dimethylamino, acetylamino, imidazol-1-yl,guavidyl, methylamino-carbonylamino, amidino,4-dimethylamino-cyclohexyl, piperazin-1-yl, 4-formyl-piperazin-1-yl orby glycylamido,

and the 1H-indolyl substituents being selected from C₂₋₃ alkylsubstituted in the ω-position by amino or by phthalimido; and

R₂ is 1,1,2,2-tetrafluoro-ethoxy or a radical of formula VII wherein

R₂ is hydrogen,

X is oxo,

n is 0 and

R₁₃ is phenyl,

and salts of such compounds having at least one salt-forming group.

More especially preferred are compounds of formula I wherein

R₁ is naphthyl or a substituted cyclic radical selected from phenyl,pyridyl and 1H-indolyl,

the phenyl substituents being selected from C₁₋₂ alkoxy, chlorine,tritluoromethoxy, nitro, cyano, from a radical of formula II wherein

m is 1 and

R₃ is hydrogen,

and from a radical of formula III wherein

R₄ is hydrogen and

R₅ is hydrogen or C₂₋₃ alkyl substituted in the ω-position by amino orby hydroxy,

the pyfidyl subsfituents being in the ortho-position with respect to thepyridine nitrogen and being selected from hydroxy, chlorine, methoxy,aminomethyl, from a radical of formula II wherein

m is 1 and

R₃ is hydrogen,

from a radical of formula III wherein

R₄ is hydrogen and

R₅ is hydrogen or C₂₋₃ alkyl substituted in the ω-position by amino orby hydroxy,

and from a radical of formula VI wherein

R₁₀ is hydrogen and

R₁₁ is amino or 4-amino-cyclohexyl, or is C₁₋₄ alkyl substituted in theω-position by amino, dimethylamino, acetylamino, imidazol-1-yl,guanidyl, methylamino-carbonylamino, amidino,4-dimethylamino-cyclohexyl, piperazin-1-yl, 4-formyl-piperazin-1-yl,glycylamido or by carboxy,

and the 1H-indolyl substituents being selected from C₂₋₃ alkylsubstituted in the ω-position by amirto or by phthalimido; and

R₂ is 1,1,2,2-tetrafluoro-ethoxy or a radical of formuh VII wherein

R₁₂ is hydrogen,

X is oxo,

n is 0 and

R₁₃ phenyl,

and salts of such compounds having at least one salt-forming group.

Most preferred are the compounds of formula I described in the Examplesand salts of such compounds having at least one salt-forming group.

The compounds of formula I and the salts of such compounds having atleast one salt-forming group are prepared in accordance with processesknown per se. The process according to the invention is effected asfollows:

a) a compound of formula VIII

    R.sub.1 --C(═O)--CH═CH--N(R.sub.14)--R.sub.15      (VIII),

wherein R₁₄ and R₁₅ are each independently of the other lower alkyl andR₁ is as defined above, functional groups present in a compound offormula VIII, with the exception of the groups participating in thereaction, being, if necessary, in protected form, or a salt of such acompound is reacted with a compound of formula IX ##STR3## wherein R₂ isas defined above, functional groups present in a compound of formula IX,with the exception of the guanidino group participating in the reaction,being, if necessary, in protected form, or with a salt of such acompound, and any protecting groups present are removed, or

b) for the preparation of a compound of formula I wherein R₂ is aradical of formula VII and R_(l) is as defined above, a compound offormula X ##STR4## wherein R₁₆ is amino and R₁ is as defined above,functional groups present in a compound of formula X, with the exceptionof the amino group participating in the reaction, being, if necessary,in protected form, is reacted with a compound of formula XI

    HO--C(═X)--(Y).sub.n --R.sub.13                        (XI),

wherein the substituents and symbols are as defined above, functionalgroups present in a compound of formula XI, with the exception of theHO--C(═X) group participating in the reaction, being, if necessary, inprotected form, or with a reactive derivative of a compound of formulaXI, and any protecting groups present are removed, or

c) for the preparation of a compound of formula I wherein R₁ is pyridyl,pyrazinyl, thiazolyl, pyrimidinyl, pyridazinyl or imidazolyl, each ofwhich is substituted by a radical of formula VI, and R₂ is as deemedabove, a compound of formula I wherein R_(l) is pyridyl, pyrazinyl,thiazolyl, pyrimidinyl, pyridazinyl or imidazolyl, each of which issubstituted by a leaving group, is reacted with an amine of formula

    HN(R.sub.10)R.sub.11                                       (XII),

wherein the substituents are as dereed above, functional groups presentin a compound of formula XII, with the exception of the amirto groupparticipating in the reaction, being, if necessary, in protected form,and any protecting groups present are removed, or

d) for the preparation of a compound of formula I wherein R₁ is any oneof the above-mentioned cyclic radicals substituted by a radical offormula lI wherein m is 1 and R₃ is hydrogen, or by a radical of formulaHI wherein R₄ and R₅ are each hydrogen, and R₂ is as defined above, acompound of formula I wherein R₁ is any one of the above-mentionedcyclic radicals substituted by cyano is hydrolysed, or

e) for the preparation of a compound of formula I wherein R₁ is apyridyl radical substituted by hydroxy, cyano or by unsubstituted orhalogen-substituted lower alkoxy and R₂ is as deemed above, in anN-oxido-pyridyl compound of formula XVI ##STR5## wherein R₁₈ isN-oxido-pyridyl bonded to a ring carbon atom and R₂ has any one of theabove-mentioned meanings, the N-oxido group is converted into a leavinggroup and the resulting leaving group is removed from the molecule bynucleophilic substitution in the ortho-position with respect to thepyridyl nitrogen using a nucleophile that introduces hydroxy, cyano orunsubstituted or halogen-substituted lower alkoxy, and, if desired, acompound of formuh I obtainable in accordance with any one of Processesa-e is converted into its salt, or an obtainable salt of a compound offormula I is converted into the free compound.

The manner in which the above-mentioned process variants are carried outis explained in detail hereinafter.

General:

The end products of formula I may comprise substiments that can also beused as protecting groups in starting materials for the preparation ofother end products of formula I. Within the scope of this text,therefore, unless the context indicates otherwise, only a readilyremovable group that is not a constituent of the particular end productof formula I desired is referred to as a "protecting group".

Protecting groups and the manner in which they are introduced andremoved are described, for example, in "Protective Groups in OrganicChemistry", Plenum Press, London, New York 1973, and in "Methoden derorganischen Chemic", Houben-Weyl, 4th edition, Vol. 15/1,Georg-Thieme-Verhg, Stuttgart 1974 and in Theodors W. Greene,"Protective Groups in Organic Synthesis", John Wiley & Sons, New York1981. A characteristic of protecting groups is that they can be readilyremoved, that is to say, without undesired secondary reactions takingplace, for example by solvolysis, reduction, photolysis or also underphysiological conditions.

Hydroxy-protecting groups are, for example, acyl radicals, such astinsubstituted or substituted, for example halogen-substituted, loweralkanoyl, such as 2,2-dichioroacetyl, or acyl radicals of carbonic acidsemiesters, especially tert-butoxycarbonyl, unsubstituted or substitutedbenzyloxycarbonyl, for example 4-nitrobenzyloxycarbonyl, ordiphenylmethoxycarbonyl, or 2-halo-lower alkoxycarbonyl, such as2,2,2-trichioroethoxycarbonyl, and also trityl or formyl, or organicsilyl or stannyl radicals, and also readily removable etherifiyinggroups, such as tert-lower alkyl, for example tert-butyl, 2-oxa- or2-thiaaliphatic or-cycloaliphatic hydrocarbon radicals, especially1-lower alkoxy-lower alkyl or 1-lower alkylthio-lower alkyl, for examplemethoxymethyl, 1-methoxy-ethyl, 1-ethoxyethyl, methylthiomethyl,1-methylthioethyl or 1-ethylthioethyl, or 2-oxa- or 2-thia-cycloalkylhaving 5 or 6 ring atoms, for example tetrahydrofuryl or2-tetrahydropyranyl or corresponding thia analogues, and alsounsubstituted or substituted 1-phenyl-lower alkyl, such as unsubstitutedor substituted benzyl or diphenylmethyl, suitable substituents of thephenyl radicals being, for example, halogen, such as chlorine, loweralkoxy, such as methoxy, and/or nitro.

A protected amino group may, for example, be in the form of a madflycleavable acylamino, arylmethylamino, etherified mercaptoamino,2-acyl-lower alk-1-en-yl-amino, silylamino or stannylamino group or inthe form of an azido group.

In a corresponding acylamino group, acyl is, for example, the acylradical of an organic carboxylic acid having, for example, up to 18carbon atoms, especially of an alkanecarboxylic acid that isunsubstituted or substituted, for example, by halogen or by aryl, or ofa benzoic acid that is unsubstituted or substituted, for example, byhalogen, lower alkoxy or by vitro, or of a carbonic acid semiester. Suchacyl groups are, for example, lower alkanoyl, such as formyl, acetyl orpropionyl, halo-lower alkanoyl, such as 2-haloacetyl, especially2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or2,2,2-tfichloro-acetyl, benzoyl that is unsubstituted or substituted,for example, by halogen, lower alkoxy or by vitro, for example benzoyl,4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or loweralkoxycarbonyl that is branched in the 1-position of the lower alkylradical or suitably substituted in the 1- or 2-position, especiallyten-lower alkoxycarbonyl, for example tert-butoxycarbonyl,arylmethoxycarbonyl having one or two aryl radicals that are preferablyphenyl that is unsubstituted or toorio- or poly-substituted, forexample, by lower alkyl, especially tert-lower alkyl, such astert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, for examplechlorine, and/or by vitro, such as unsubstituted or substitutedbenzyloxycarbonyl, for example 4-nitrobenzyloxycarbonyl, or substituteddiphenylmethoxycarbonyl, for example benzhydryloxycarbonyl ordi(4-methoxyphenyl)methoxycarbonyl, aroylmethoxycarbonyl wherein thearoyl group is preferably benzoyl that is unsubstituted or substituted,for example, by halogen, such as bromine, for examplephenacyloxycarbonyl, 2-halo-lower alkoxyearbonyl, for example2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or2-iodoethoxycarbonyl, or 2-(trisubstituted silyl)ethoxycarbonyl whereinthe substituents are each independently of the others an aliphatic,araliphatic, cycloaliphatic or aromatic hydrocarbon radical that isunsubstituted or substituted, for example, by lower alkyl, lower alkoxy,aryl, halogen or by vitro, and contains up to 15 carbon atoms, such ascorresponding unsubstituted or substituted lower alkyl, phenyl-loweralkyl, cycloalkyl or phenyl, for example 2-tri-loweralkylsilylethoxycarbonyl, such as 2-trimethylsilylethoxycarbonyl or2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or2-triaryisilylethoxycarbonyl, such as 2-triphenyisilylethoxycarbonyl.

Other acyl radicals suitable as amino-protecting groups are alsocorresponding radicals of organic phosphoric, phosphortic or phosphinicacids, such as all-lower alkylphosphoryl, for exampledimethylphosphoryl, diethylphosphoryl, di-n-propylphosphoryl ordiisopropylphosphoryl, dicycloalkylphosphoryl, for exampledicyclohexylphosphoryl, unsubstituted or substituted diphenylphosphoryl,for example diphenylphosphoryl, unsubstituted or substituted, forexample nitro-substituted, di(phenyl-lower alkyl)phosphoryl, for exampledibenzylphosphoryl or di(4-nitrobenzyl)phosphoryl, unsubstimted orsubstituted phenyloxyphenylphosphonyl, for examplephenyloxyphenylphosphonyl, di-lower alkylphosphinyl, for examplediethylphosphinyl, or tinsubstituted or substituted diphenylphosphinyl,for example diphenylphosphinyl.

In an arylmethylamino group that is a mono-, di- or, especially,tri-arylmethylamino group, the aryl radicals are especiallyunsubstituted or substituted phenyl radicals. Such groups are, forexample, benzyl-, diphenylmethyl- and, especially, trityl-amino.

An etherfiled mercapto group in an amino group protected by such aradical is especially arylthio or aryl-lower alkylthio wherein aryl isespecially phenyl that is unsubstituted or substituted, for example, bylower alkyl, such as methyl or tert-butyl, lower alkoxy, such asmethoxy, halogen, such as chlorine, and/or by nitro. A correspondingamino-protecting group is, for example, 4-nitrophenylthio.

In a 2-acyl-lower alk-1 -en-1-yl radical that can be used as anamino-protecting group, acyl is, for example, the corresponding radicalof a lower alkanecarboxylic acid, of a benzoic acid that isunsubstituted or substituted, for example, by lower alkyl, such asmethyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such aschlorine, and/or by nitro, or especially of a carbonic acid semiester,such as a carbonic acid lower alkyl semiester. Corresponding protectinggroups are especially 1-lower alkanoyl-prop-1 -en-2-yl, for example1-acetyl-prop-1-en-2-yl, or 1-lower alkoxycarbonyl-prop-1-en-2-yl, forexample 1-ethoxycarbonyl-prop-1 -en-2-yl.

Preferred amino-protecting groups are acyl radicals of carbonic acidsemiesters, especially tert-butoxycarbonyl, benzyloxycarbonyl that isunsubstituted or substituted, for example, as indicated, for example4-nitro-benzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halo-loweralkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, and also tritylor formyl. The removal of the protecting groups that are notconstituents of the desired end product of formula I is effected in amanner known per se, for example by solvolysis, especially hydrolysis,alcoholysis or acidolysis, or by means of reduction, especiallyhydrogenolysis or chemical reduction, as appropriate stepwise orsimultaneously.

A protected amino group is freed in a manner known per se and, dependingon the nature of the protecting groups, in various manners, preferablyby solvolysis or reduction. 2-halo-lower alkoxycarbonylamino (whereappropriate after conversion of a 2-bromo-lower alkoxycarbonylaminogroup into a 2-iodo-lower alkoxycarbonylamino group),aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can becleaved, for example, by treatment with a suitable chemical reducingagent, such as zinc in the presence of a suitable carboxylic acid, suchas aqueous acetic acid. Aroylmethoxycarbonylamino can also be cleaved bytreatment with a nucleophilic, preferably salt-forming reagent, such assodium thiophenolate, and 4-nitro-benzyloxycarbonylamino also bytreatment with an alkali metal dithionite, for example sodiumdithionite. Unsubstituted or substituted diphenylmethoxycarbonylamino,tert-lower alkoxycarbonylamino or 2-tri-substitutedsilylethoxycarbonylamino can be cleaved by treatment with a suitableacid, for example formic acid or trifiuoroacetic acid, unsubstituted orsubstituted benzyloxycarbonylamino, for example, by hydrogenolysis, thatis to say by treatment with hydrogen in the presence of a suitablehydrogenation catalyst, such as a palladium catalyst, unsubstituted orsubstituted triarylmethylamino or formylamino, for example, by treatmentwith an acid, such as a mineral acid, for example hydrochloric acid, oran organic acid, for example formic, acetic or trifluoroacetic acid,where appropriate in the presence of water, and an amino group protectedby an organic silyl group can be freed, for example, by hydrolysis oralcoholysis. An amino group protected by 2-haloacetyl, for example2-chloroacetyl, can be freed by treatment with thiourea in the presenceof a base, or with a thiolate salt, such as an alkali metal thiolate, ofthe thiourea, and subsequent solvolysis, such as alcoholysis orhydrolysis, of the resulting condensation product. An amino groupprotected by 2-substituted silylethoxycarbonyl can also be convertedinto the free amino group by treatment with a hydrofluoric acid saltyielding fluoride anions.

A hydroxy group protected by a suitable acyl group, an organic silylgroup or by unsubstituted or substituted 1-phenyl-lower alkyl is freedanalogously to a correspondingly protected amino group. Hydroxyprotected by unsubstituted or substituted 1-phenyl-lower alkyl, forexample benzyl, is freed preferably by catalytic hydrogenation, forexample in the presence of a palladium-on-carbon catalyst. A hydroxygroup protected by 2,2-dichloroacetyl is freed, for example, by basichydrolysis, and a hydroxy group etherified by tert-lower alkyl or by a2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical isfreed by acidolysis, for example by treatment with a mineral acid or astrong carboxylic acid, for example trifluoroacetic acid. Hydroxyetherified by an organic silyl radical, for example trimethylsilyl, canalso be freed by a hydrofluoric acid salt yielding fluoride anions, forexample terfrabutylammonium fluoride.

Process a:

Preferably, R₁₄ and R₁₅ are each methyl

Free functional groups in a compound of formula VIII, which areadvantageously protected by readily removable protecting groups, areespecially amino groups in the radical R_(l) and the imino group of1H-indolyl. The imino group can be protected, for example, by benzyl.

Free functional groups in a compound of formula IX, which areadvantageously protected by readily removable protecting groups, areespecially amino groups, but also hydroxy and carboxy groups.

A salt of a compound of formula VIII or IX is preferably an acidaddition salt, for example a nitrate or one of the acid addition saltsmentioned for the end products of formula I.

The reaction is carried out in a suitable solvent or dispersing agent,for example a suitable alcohol, such as 2-methoxy-ethanol or a suitablelower alkanol, for example isopropanol or isobutanol, at a temperatureof from room temperature (approximately 20° C.) to 150° C., for exampleunder reflux. Especially when the compound of formula VIII is used inthe form of a salt, that salt is converted into the free compound,preferably/in situ, by the addition of a suitable base, such as analkali metal hydroxide, for example sodium hydroxide.

The starting material of formula VIII is obtained by reacting a compoundof formula XIII ##STR6## wherein R₁ is as defined above, with a compoundof formula XIV ##STR7## wherein R₁₇ and R₁₈ are each lower alkyl and theother substituents are as defined above, analogously to the proceduredescribed in the European Patent Application having the publicationnumber 233 461. Typical representatives of a compound of formula XIIIare N,N-dimethylformamide dimethylacetal and N,N-dimethylformamidediethylacetal. The reaction is effected while heating the reactants offormulae XKI and XIV, for example for 1-24 hours, in the absence or, ifnecessary, in the presence of a solvent, at a temperature ofapproximately from 50° C. to 150° C.

Alternatively, the starting material of formula VIII can also beobtained by reacting a compound of formula XIII with formic acid ethylester of the formula H--C(═O)--O--CH₂ --CH₃ and reacting the resultingproduct with an amine of the formula H--N(R₁₄)--R₁₅ wherein thesubstituents are as defined above.

The starting material of formula IX is obtained in the form of an acidaddition salt by reacting an aniline derivative of formuh XV ##STR8##wherein R₂ is as defined above, with cyanamide (NC--NH₂). The reactionis effected in a suitable solvent or dispersing agent, for example asuitable alcohol, for example a suitable lower alkanol, such as ethanol,for example

α) in the presence of equimolar amounts of the salt-forming acid, forexample nitric acid, or

β) in the presence of a clear, for example 60%, excess of a mineralacid, such as hydrochloric acid, an ammonium salt of the desiredsalt-forming acid, for example ammonium nitrate, being added when thereaction is complete,

at a temperature of from room temperature to 150° C., for example underreflux.

Process b:

Free functional groups in a compound of formula X or XI, which areadvantageously protected by readily removable protecting groups, areespecially amino groups but also hydroxy and carboxy groups which arenot to participate in the desired reaction, for example amino in theradical R₁.

A reactive derivative of a compound of formula XI wherein X is oxo isespecially a reactive (activated) ester, a reactive anthydride or areactive cyclic amide. The same applies to derivatives wherein X has anyone of the other above-mentioned meanings.

Reactive (activated) esters of an acid of formula XI are especiallyesters unsaturated at the linking carbon atom of the esterifyingradical, for example of the vinyl ester type, such as vinyl estersthemselves (which can be obtained, for example, by transesterifying acorresponding ester with vinyl acetate; activated vinyl ester method),carbamoyl vinyl esters (which can be obtained, for example, by treatingthe corresponding acid with an isoxazolium reagent; 1,2-oxazolium orWoodward method), or 1-lower alkoxyvinyl esters (which can be obtained,for example, by treating the corresponding acid with a loweralkoxyacetylene; ethoxyacetylene method), or esters of the amidino type,such as N,N'-di-substituted amidino esters (which can be obtained, forexample, by treating the corresponding acid with a suitableN,N'-di-substituted carbodiimide, for exampleN,N'-dicyclohexylcarbodiimide; carbo diimide method), orN,N-di-substituted amidino esters (which can be obtained, for example,by treating the corresponding acid with an N,N-di-substituted cyanamide;cyanamide method), suitable aryl esters, especially phenyl esterssuitably substituted by electron-attracting substituents (which can beobtained, for example, by treating the corresponding acid with asuitably substituted phenol, for example 4-nitrophenol,4-methylsulfonyl-phenol, 2,4,5-trichlorophenol,2,3,4,5,6-pentachlorophenol or 4-phenyldiazophenol, in the presence of acondensation agent, such as N,N'-dicyclohexylcarbodmide; activated arylesters method), cyanomethyl esters (which can be obtained, for example,by treating the corresponding acid with chloroacetonitrile in thepresence of a base; cyanomethyl esters method), thio esters, especiallyunsubstituted or substituted, for example nitro-substituted, phenylthioesters (which can be obtained, for example, by treating thecorresponding acid with unsubstituted or substituted, for examplenitro-substituted, thiophenols, inter alia by the anthydride orcarbodiimide method; activated thiol esters method), amino or amidoesters (which can be obtained, for example, by treating thecorresponding acid with an N-hydroxy-amino or N-hydroxy-amido compound,for example N-hydroxy-succinimide, N-hydroxy-piperidine,N-hydroxy-phthaliraide or 1-hydroxy-benzotriazole, for example by theanhydride or carbodiimide method; activated N-hydroxy esters method) orsilyl esters (which can be obtained, for example, by treating thecorresponding acid with a silylating agent, for examplehexamethyldisilazane, and which react readily with hydroxy groups butnot with amino groups).

Anhydrides of an acid of formula XI may be symmetric or preferably mixedanhydrides of those acids, for example anhydrides with inorganic acids,such as acid halides, especially acid chlorides (which can be obtained,for example, by treating the corresponding acid with thionyl chloride,phosphorus pentachloride or oxalyl chloride; acid chloride method),azides (which can be obtained, for example, from a corresponding acidester by way of the corresponding hydrazide and treatment thereof withnitrous acid; azide method), anhydrides with carbonic acidsemi-derivatives, such as with corresponding esters, for examplecarbonic acid lower alkyl semiesters (which can be obtained, forexample, by treating the corresponding acid with haloformic acid loweralkyl esters, such as chloroformic acid lower alkyl esters, or with a1-lower alkoxycarbonyl-2-1-lower alkoxy-1,2-dihydroquinoline, forexample 1-lower alkoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; mixedO-alkylcarbonic acid anhydrides method), or anhydrides withdihalogenated, especially dichlorinated, phosphoric acid (which can beobtained, for example, by treating the corresponding acid withphosphorus oxychloride; phosphorus oxychloride method), or anhydrideswith organic acids, such as mixed anthydrides with organic carboxylicacids (which can be obtained, for example, by treating the correspondingacid with an unsubstituted or substituted lower alkane- orphenylalkane-carboxylic acid halide, for example phenylacetic acidchloride, pivalic acid chloride or trifluoroacetic acid chloride; mixedcarboxylic acid anhydrides method) or with organic sulfonic acids (whichcan be obtained, for example, by treating a salt, such as an alkalimetal salt, of the corresponding acid with a suitable organic sulfonicacid halide, such as a lower alkane- or aryl-sulfonic acid chloride, forexample methane- or p-toluene-sulfonic acid chloride; mixed sulfonicacid anhydrides method) and symmetric anhydrides (which can be obtained,for example, by condensing the corresponding acid in the presence of acarbodiimide or 1-diethylaminopropyne; symmetric anhydrides method).

Suitable cyclic amides are especially amides having five-membereddiazacycles of aromatic character, such as amides with imidazoles, forexample imidazole (which can be obtained, for example, by treating thecorresponding acid with N,N'-carbonyldiimidazole; imidazolide method),or pyrazoles, for example 3,5-dimethylpyrazole (which can be obtained,for example, by way of the acid hydrazide by treatment withacetylacetone; pyrazolide method).

Derivatives of acids of formula XI that are used as acylating agents canalso be formed in situ. For example, N,N'-di-substituted amidino esterscan be formed in situ by reacting a mixture of the starting material offormula X and the acid used as acylating agent in the presence of asuitable N,N-di-substituted carbodiimide, for exampleN,N'-dicyclohexylcarbodiimide. In addition, amino or amido esters oramido esters of the acids used as acylating agents can be formed in thepresence of the starting material of formula X to be acylated, byreacting a mixture of the corresponding acid and amino startingmaterials in the presence of an N,N'-di-substituted carbodiimide, forexample N,N'-dicyclohexylcarbodiimide, and of an N-hydroxy-amine orN-hydroxy-amide, for example N-hydroxysuccinimide, where appropriate inthe presence of a suitable base, for example 4-dimethylaminopyridine.

The reaction is preferably carried out by reacting a reactive carboxylicacid derivative of a. compound of formula XI with a compound of formulaX, the amino or hydroxy group participating in the reaction being infree form.

The reaction can be carried out in a manner known per se, the reactionconditions depending especially upon whether and how the carboxy groupof the acylating agent has been activated, generally in the presence ofa suitable solvent or diluent or a mixture thereof, and, if necessary,in the presence of a condensation agent which, for example when thecarboxy group participating in the reaction is in the form of ananhydride, may also be an acid-binding agent, with cooling or heating,for example in a temperature range of from approximately -30° C. toapproximately +150° C., especially approximately from 0° C. to +100° C.,preferably from room temperature (approximately +20° C.) to +70° C.,open or closed reaction vessel and/or in the atmosphere of an inert gas,for example nitrogen. Customary condensation agents are, for example,carbodiimides, for example N,N'-diethyl-, N,N'-dipropyl-,N,N'-dicyclohexyl- or N-ethyl-'-(3-dimethylaminopropyl)-carbodiimide,suitable carbonyl compounds, for example carbonyldiimidazole, or1,2-oxazolium compounds, for example2-ethyl-5-phenyl-1,2-oxazolium-3'-sulfonate and2-tert-butyl-5-methyl-isoxazolium perchlorate, or a suitable acylaminocompound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.Customary acid-binding condensation agents are, for example, alkalimetal carbonates or hydrogen carbonates, for example sodium or potassiumcarbonate or hydrogen carbonate (customafily together with a sulfate),or organic bases, such as customarily pyridine or sterically hinderedtri-lower alkylamines, for example N,N-dftsopropyl-N-ethylamine.

The starting material of formula X is obtained by reducing the nitrogroup(s) in a compound of formula I wherein R₂ is nitro. The reductionmay be carried out, for example, by catalytic hydrogenation in asuitable solvent, such as a suitable acyclic or cyclic ether, such as intetrahydrofuran. The hydrogenation catalyst used is preferablypalladium/activated carbon (5%) and the hydrogenation is in that casepreferably carried out under normal pressure.

Process c:

A leaving group is reactive esterified hydroxy, for example hydroxyesterified by a strong inorganic or organic acid, such as by a mineralacid, for example a hydrohalic acid, such as hydrochloric, hydrobromicor hydriodic acid, also sulfuric acid or a sulfuryl halide, for examplesulfuryl fluoride, or by a strong organic sulfonic acid, such as a loweralkanesulfonic acid that is unsubstituted or substituted, for example,by halogen, such as fluorine, or an aromatic sulfonic acid, for examplea benzenesulfonic acid that is unsubstituted or substituted by loweralkyl, such as methyl, halogen, such as bromine, and/or by nitro, forexample a methanesulfonic, trifluoromethanesulfonic or p-toluenesulfonicacid. A preferred leaving group is halogen, such as, especially,chlorine.

The reaction is preferably carried out in the presence of an excess ofthe amine of formula XII, which can, where appropriate, also be used assolvent, and, if necessary, in the presence of an inert solvent, such asdimethyl sulfoxide, at a temperature of from room temperature to +150°C., for example at 100° C.

Process d:

The hydrolysis of cyano to carbamoyl can be carried out in the presenceof a suitable weak base, such as an alkali metal carbonate, for examplesodium carbonate. In order to prevent the hydrolysis from continuingpartially to carboxy, it is recommendable to carry out the hydrolysiswith hydrogen peroxide in the presence of a suitable olefin, such aspreferably a lower alkene, for example 1-hexene, in the presence of analkali metal carbonate, for example sodium carbonate, in a suitablesolvent, such as an alcohol, such as preferably ethanol, at roomtemperature.

The hydrolysis of cyano to carboxy is carried out in a suitable solvent,such as an alcohol, such as ethanol, for example in the presence of asuitable base, such as aqueous sodium hydroxide solution, attemperatures of from room temperature to +150° C., for example at 60° C.

Process e:

The conversion of the N-oxido group into a leaving group is effected,for example, by reaction with a suitable reactive carboxylic or sulfonicacid derivative, for example with a suitable lower alkanoic acidchloride, lower alkanoic acid anhydride, such as acetic arthydride,N,N-dimethyl-carbamoyl chloride, toluenesulfonyl chloride,methanesulfonyl chloride or trifluoromethanesulfonyl chloride. Anucleophile that introduces cyano is, for example, a suitable silylcyanide, such as tri-lower alkyl-silyl cyanide, for exampletrimethyisilyl cyanide. A nucleophile that introduces lower alkoxy orhalogen-substituted lower alkoxy is, for example, a corresponding loweralkanol, or a suitable metal salt, such as, for example, an alkali metalsalt, thereof, that is to say, a corresponding lower alkanolate. Hydroxycan be introduced, for example, by reacting a compound of formula XVIwith a suitable acid arthydride and hydrolysing the resultingintermediate. Process e is carried out in a suitable solvent, such asacetonitrile, at temperatures of approximately from 0° C. to 150° C.,preferably approximately from room temperature to 100° C.

The starting material of formula XVI is obtained by oxidising acorresponding pyridyl compound with a suitable oxidising agent, such asa suitable peracid, for example a suitable perbenzoic acid, such asespecially m-chloro-perbenzoic acid, in an inert solvent, such asmethylene chloride, at room temperature.

Acid addition salts of compounds of formula I are obtained in customarymanner, for example by treatment with an acid or a suitable anionexchange reagent.

Acid addition salts can be converted in customary manner into the freecompounds, for example by treatment with a suitable basic agent.

Mixtures of isomers can be separated into the individual isomers in amanner known per se, for example by fractional crystallisation,chromatography, etc.

The processes described above, including the processes for removingprotecting groups and the additional process measures are, unlessotherwise indicated, carried out in a manner known per se, for examplein the presence or absence of preferably inert solvents or diluents, ifnecessary in the presence of condensation agents or catalysts, atreduced or elevated temperature, for example in a temperature range offrom approximately -20° C. to approximately 150° C., especially fromapproximately 0° C. to approximately +70° C., preferably fromapproximately +10° C. to approximately +50° C., principally at roomtemperature, in a suitable vessel and, if necessary, in an inert gasatmosphere, for example a nitrogen atmosphere.

Taking into account all the substituents in the molecule, if necessary,for example if readily hydrolysable radicals are present, especiallymild reaction conditions are to be used, such as short reaction times,the use of mild acidic or basic agents in low concentration,stoichiometric ratios, and the selection of suitable catalysts,solvents, temperature conditions and/or pressure conditions.

The invention relates also to those forms of the process in which acompound obtainable as intermediate at any stage of the process is usedas starting material and the remaining process steps are carried out orthe process is discontinued at any stage or a starting material isformed under the reaction conditions or is used in the form of areactive derivative or salt. The starting materials used are preferablythose which, according to the process, result in the compounds describedabove as being especially valuable.

The present invention relates also to novel starting materials and/orintermediates and to processes for the preparation thereof. The startingmaterials used and the reaction conditions chosen are preferably suchthat the compounds described in this Application as being especiallypreferred are obtained.

The invention relates also to a method of treating warm-blooded animalssuffering from a tumour disease, which method comprises administering towarm-blooded animals requiring such treatment an amount that iseffective in inhibiting tumours of a compound of formula I or of apharmaceutically acceptable salt thereof. The invention relates also tothe use of a compound of formula I or of a pharmaceutically acceptablesalt thereof in the inhibition of protein kinase C in warm-bloodedanimals or in the preparation of pharmaceutical compositions for use inthe therapeutic treatment of the human or animal body. Depending on thespecies, age, individual condition, mode of administration and theparticular clinical picture, effective doses, for example daily doses ofapproximately 1-1000 mg, especially 50-500 mg, are administered to awarm-blooded animal of approximately 70 kg body weight.

The invention relates also to pharmaceutical compositions comprising aneffective amount, especially an mount effective in the prophylaxis ortreatment of one of the above-mentioned disorders, of the activeingredient together with pharmaceutically acceptable carriers that aresuitable for topical, enteral, for example oral or rectal, or parenteraladministration and that may be inorganic or organic, solid or liquid.There are used for oral administration especially tablets or gelatincapsules that comprise the active ingredient together with diluents, forexample lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/orglycerol, and/or lubricants, for example silica, talc, stearic acid orsalts thereof, such as magnesium or calcium stearate, and/orpolyethylene glycol Tablets may also comprise binders, for examplemagnesium aluminium silicate, starches, such as corn, wheat or ricestarch, gelatin, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone, and, if desired, disintegrators, for examplestarches, agar, alginic acid or a salt thereof, such as sodium alginate,and/or effervescent mixtures, or adsorbents, dyes, flavourings andsweeteners. It is also possible to use the pharmacologically activecompounds of the present invention in the form of parenterallyadministrable compositions or in the form of infusion solutions. Suchsolutions are preferably isotonic aqueous solutions or suspensionswhich, for example in the case of lyophilised compositions that comprisethe active ingredient alone or together with a carrier, for examplemannitol, can be made up prior to use. The pharmaceutical compositionsmay be sterilised and/or may comprise excipients, for examplepreservatives, stabilisers, wetting agents and/or emulsifiers,solubilisers, salts for regulating the osmotic pressure and/or buffers.The present pharmaceutical compositions, which may, if desired, compriseother pharmacologically active substances, such as antibiotics, areprepared in a manner known per se, for example by means of conventionalmixing, granulating, confectioning, dissolving or lyophilsing processes,and comprise approximately from 1% to 100%, especially fromapproximately 1% to approximately 20%, active ingredient(s).

The following Examples illustrate the invention without limiting it inany way. The R_(f) values are determined on silica gel thin-layer plates(Merck, Darmstadt, Gemany). The ratio of the eluants in the eluantmixtures used is indicated in pans by volume (v/v) and temperatures areindicated in degrees Celsius.

Abbreviations:

DMF: dimethylformamide

DMSO: dimethyl sulfoxide

FAB-MS: Fast Atom Bombardment Mass Spectrum

HV: high vacuum

rotovapor: rotary evaporator

RT: room temperature

h: hour(s)

THF: tetrahydrofuran

EXAMPLE 1

1189.4 mg (0.75 mmol) of 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidinenitrate are added to a solution of 200 mg (0.75 mmol) of3-dimethylamino-1-(3,4,5-trimethoxy-phenyl)-2-propen-1-one in 11.5 ml of1-propanol. After the addition of 33.2 mg (0.83 mmol) of sodiumhydroxide, the reaction mixture is boiled under reflux for 23 hours.After cooling to RT, the reaction product is isolated by filtration andwashed with 1-propanol and water. After drying at 60° C. under HV,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3,4,5-trimethoxyphenyl)-2-pyrimidineamineis obtained; R_(f) =0.75 (methylene chloride:methanol=9:1), FAB-MS: 454(M⁺ +1), m.p. 132° C.

The starting material is obtained in the following manner:

Stage 1.1: 10.1 g (240 mmol) of cyanamide (50% in water) are added to asuspension of 25.2 g (120 mmol) of3-(1,1,2,2-tetrafluoro-ethoxy)-aniline in 125 ml of ethanol. 16.3 ml ofhydrochloric acid (conc., 192 mmol) are then added to the brown solutionand the reaction mixture is heated under reflux for 19 h. After coolingto RT, the reaction mixture is concentrated under reduced pressure andthe residue is dissolved in 80 ml of water. After the addition of 19.2 g(240 mmol) of ammonium nitrate, the product is isolated by filtration,then washed with water and dried at 60° under I-HV.3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate is obtained;m.p. 132°-14133°.

Stage 1.2: 0.5 g (2.38 mmol) of 3,4,5-trimethoxyacetophenone is stirredin 2.7 ml of dimethylformamide diethylacetal for 96 h at 110°. Aftercooling to 0°, filtering and drying,3-dimethylamino-1-(3,4,5-trimethoxy-phenyl)-2-propen-1-one is obtained;¹ H-NMR (DMSO): 2.9 (3H,s), 3.1 (3H,s), 3.7 (3H,s), 3.85 (6H,s), 5.83(1H,d), 7.19 (2H,s), 7.7 (1H,d).

EXAMPLE 2

21.28 g (84.7 mmol) of 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidinenitrate are added to a solution of 17.4 g (84.7 mmol) of3-dimethylamino-1-(3-methoxy-phenyl)-2-propen-1-one in 100 ml of2-propanol. After the addition of 3.72 g (93.2 mmol) of sodiumhydroxide, the reaction mixture is boiled under reflux for 21.3 h. Aftercooling to RT, the product is isolated by filtration and washed with1-propanol and water. After drying at 60° under HV,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-methoxy-phenyl)-2-pyrimidineamineis obtained; R_(f) =0.7 (methylene chloride:methanol =9:1), FAB-MS: 397(M⁺ +1), m.p. 103°-104°.

The starting material is obtained in the following manner:

Stage 2.1: 0.5 g (3.3 mmol) of 3-methoxyacetophenone is stirred in 3.8ml of dimethylformanaide diethylacetal for 4.5 h at 110°. Afterconcentration using a rotovapor and chromatography (methylenechloride:methanol=98:2),3-dimethylamino-1-(3-methoxy-phenyl)-2-propen-1-one is obtained; ¹ H-NMR(DMSO): 2.9 (3H, s), 3.1 (3H,s), 3.8 (3H,s), 5.8 (1H,d), 7.05 (1H,d),7.4 (3H,m), 7.7 (1H,d).

EXAMPLE 3

539 mg (2.15 mmol) of 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidinenitrate are added to a solution of 450 mg (2.15 mmol) of3-dimethylamino-1-(4-chloro-phenyl)-2-propen-1-one in 5.5 ml of2-propanol. After the addition of 94.5 mg (2.36 mmol) of sodiumhydroxide, the reaction mixture is boiled under reflux for 29 h. Aftercooling to RT, the product is isolated by filtration and washed with1-propanol and water. After drying at 60° under HV,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(4-chloro-phenyl)-2-pyrimidineamineis obtained; R_(f) =0.45 (methylene chloride:methanol =98:2), MS: 397(M⁺), m.p. 133°-135°.

The starting material is obtained in the following manner:

Stage 3.05 g (3.23 mmol) of 4-chloroacetophenone are stirred in 3.6 mlof dimethylformamide diethylacetal for 17.5 h at 110°. After cooling,precipitation is effected with hexane and the precipitate is isolated byfiltration and dried. 3-dimethylamino-1(4-chloro-phenyl)-2-propen-1-oneis obtained; ¹ H-NMR (DMSO): 2.9 (3H,s), 3.1 (3H,s), 5.8 (1H,d), 7.5(2H,m), 7.75 (1H,d), 7.95 (2H,m).

EXAMPLE 4

926.1 mg (3.69 mmol) of 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidinenitrate are added to a solution of 801.1 mg (3.69 mmol) of3-dimethylamino-1-(3-ethoxy-phenyl)-2-propen-1-one in 10 ml of2-propanol. After the addition of 162.2 mg (4.05 mmol) of sodiumhydroxide, the reaction mixture is boiled under reflux for 20 h. Aftercooling to RT, the reaction product is isolated by filtration and washedwith 1-propanol, ethyl acetate and water. After chromatography(hexane:ethyl acetate=7:3),N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-ethoxy-phenyl)-2-pyrimidineamineis obtained; R_(f) =0.72 (methylene chloride:methanol=98:2), m.p.88°-96°.

The starting material is obtained in the following manner:

Stage 4.1: 0.625 mg (3.67 mmol) of 3-hydroxy-acetophenone is stirred in4.0 ml of dimethylformamide diethylacetal for 21 h at 110°. Aftercooling, filtering, washing with hexane and drying at 60° under HV,3-dimethylamino-1-(3-ethoxy-phenyl)-2-propen-1-one is obtained; ¹ H-NMR(DMSO): 1.35 (3H,t), 2.9 (3H,s), 3.1 (3H,s), 4.1 (2H,q), 5.8 (1H,d),7.05 (1H,d), 7.4 (3H,m), 7.7 (1H,d).

EXAMPLE 5

553 mg (2.2 mmol) of 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidinenitrate are added to a solution of 570.7 mg (2.2 mmol) of3-dimethylamino-1-(3-trifluoro-methoxy-phenyl)-2-propen-1-one in 6 ml of2-propanol. After the addition of 97 mg (2.42 mmol) of sodium hydroxide,the reaction mixture is boiled under reflux for 30 h. After cooling toRT, the product is isolated by filtration and washed with 1-propanol andwater. After drying at 60° under HV,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-tri-fluoromethoxy-phenyl)-2-pyrimidineamineis obtained; R_(f) =0.77 (methylene chloride:methanol=98:2); FAB-MS: 448(M⁺ +1), m.p. 98°-100°.

The starting material is obtained in the following manner:

Stage 5.1: 0.51 g (2.45 mmol)of 3-trifluoromethoxy-acetophenone isstirred in 2 ml of dimethylformamide diethylacetal for 23 h at 110°.After concentration using a rotovapor and chromatography(toluene:acetone=95:5),3-dimethylamino-1-(3-trifluoromethoxyphenyl)-2-propen-1-one is obtained;¹ H-NMR (DMSO): 2.9 (3H,s), 3.1 (3H,s), 5.9 (1H,d), 7.5-7.8 (4H,m), 8.0(1H,d).

EXAMPLE 6

100 mg (0.25 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamineare dissolved in 1 ml of dimethyl sulfoxide, and 0.2 ml ofethylenediamine is added. After stirring for 22 h at 100°, the reactionmixture is concentrated and chromatographed (methylenechloride:methanol:concentrated ammonia solution=90:10:1).N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-amino-ethyl-amino)-4-pyridyl]-2-pyrimidineamineis obtained; FAB-MS: 423 (M⁺ +H), R_(f) =0.1 (methylenechloride:methanol:concentrated ammonia solution=90:10:1).

The starting material is obtained in accordance with Example 21.

EXAMPLE 7

Analogously to Example 6 there is obtained from 100 mg (0.251 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamineand 2 ml of 3-dimethylamino-1-propylamineN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2(3-dimethylamino-propyl-amino)-4-pyridyl]-2-pyrimidineamine;MS: 464 (M⁺), 419, 406, R_(f) =0.2 (methylenechloride:methanol:concentrated ammonia solution=80:20:1).

EXAMPLE 8

Analogously to Example 6 there is obtained from 50 mg (0.125 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamineand 2 ml of 1,4-diaminobutaneN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-4-[2-(4-amino-butylamino)4-pyridyl]-2-pyrimidineamine; MS(FAB): 451 (M⁺ +H), R_(f) =0.05(methylene chloride:methanol:concentrated ammonia solution=80:20:1).

EXAMPLE 9

Analogously to Example 6 there is obtained from 100 mg (0.251 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineaminedissolved in 1 ml of dimethylformamide and 0.33 ml (2.5 mmol) of1-(2-amino-ethyl)-piperazine N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-{2-[2-(4-formyl-piperazinyl)-ethyl-amino]-4-pyridyl}-2pyrimidineamine;MS (FAB): 520 (M⁺ +H), R_(f) =0.4 (methylenechloride:methanol:concentrated ammonia solution=80:20:1).

EXAMPLE 10

Analogously to Example 6 there is obtained from 174 mg (0.44 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamineand 3 ml of 1-(2-amino-ethyl)-piperazineN-[3-(1,1,2-2-tetrafluoro-ethoxy)-phenyl]-4-[2(2(2-piperazinyl-ethyl-amino)-4-pyridyl]-2-pyrimidineamine; MS (FAB): 492(M⁺ +H). R_(f) =0.1 (methylene chloride:methanol:concentrated ammoniasolution=80:20:1).

EXAMPLE 11

Analogously to Example 6 there is obtained from 100 mg (0.25 1 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamineand 2 ml of cis/trans-1,4-diamino-cyclohexaneN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(cis/trans-4-amino-cyclohexylamino)-4-pyridyl]-2-pyrimidineamine;MS: 476 (M⁺), 459, 418, R_(f) =0.17 (methylenechloride:methanol:concentrated ammonia solution=80:20:1).

The pure cis-isomer is obtained by repeated chromatographic separationof the cis/trans mixture obtained above in the eluant system methylenechloride/methanol/concentrated ammonia solution (80:20:1).

EXAMPLE 12

Analogously to Example 6 there is obtained from 100 mg (0.251 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]4-(2-chloro-4-pyridyl)-2-pyrimidineamineand 0.8 g (5.2 mmol) of cis/trans-4-dimethylamino-cyclohexyl-methylamineN-[-3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-{(cis/trans-4-dimethylamino-cyclohexyl)-methylamino}-4-pyridyl]-2-pyrimidineamine;MS(FAB): 519 (M⁺ +H), R_(f) =0.2 (methylenechloride:methanol:concentrated ammonia solution=80:20:1).

EXAMPLE 13

Analogously to Example 6 there is obtained from 100 mg (0.251 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-5-pyridyl)-2-pyrimidineamineand 0.2 ml of ethylenediamineN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-aminoethylamino)-5-pyridyl]-2-pyrimidineamine;MS(FAB): 432, R_(f) =0.1 (methylene chloride:methanol:concentratedammonia solution=90:10:1).

The starting material is obtained in the following manner:

Stage 13.1: 31.91 g (230.3 mmol) of 2-chloro-5-cyano-pyridine are placedin 1.6 liters of diethyl ether under nitrogen, and 155 ml (22% intetrahydrofuran, 456 mmol) of methylmagnesium chloride are added. Thered suspension is stirred for 14 h at RT, poured onto 1.6 liters ofice/water and 320 ml of concentrated hydrochloric acid and stirred for14 h at RT. Extraction with diethyl ether and methylene chloride, dryingwith MgSO₄ and concentration give 5-acetyl-2-chloro-pyridine; R_(f)=0.46 (hexane:ethyl acetate=2:1).

Stage 13.2: 15.4 g (98.7 mmol) of 5-acetyl-2-chloro-pyridine are stirredfor 1 h at 110° with 100 ml of dimethylformamide diethylacetal. Aftercooling to 0° filtering and drying at 60°, under HV,3-dimethylamino-1-(2-chloro-5-pyridyl)-2-propen-1-one is obtained; ¹H-NMR (DMSO): 2.98 (3H,s), 3.2 (3H,s), 5.9 (1H,d), 7.6 (1H,d), 7.8(1H,d), 8.3 (1H, m), 8.9 (1H,m).

Stage 13.3: 9.22 g (43.8 mmol)of3-dimethylamino-1-(2-chloro-5-pyridyl)-2-propen-1-one is suspended in 88ml of 2-propanol. 11 g (43.8 mmol) of3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate and 1.93 g (48.4mmol) of sodium hydroxide are added and the reaction mixture is boiledunder reflux for 19 h. After cooling to RT, the product is isolated byfiltration, washed with 2-propanol and water and dried at 50° under HV.N[3(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-5-pyridyl)-2-pyrimidineamineis obtained; FAB-MS: 399 (M⁺ +H), m.p. 182°-184°.

EXAMPLE 14

Analogously to Example 6 there is obtained from 100 mg (54.2 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-5-pyridyl)-2-pyrimidineamineand 2 ml of cis/trans-1,4-diamino-cyclohexane N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(cis/trans-4-amino-cyclohexyl-amino)-5-pyridyl]-2-pyrimidineamine;FAB-MS: 477 (M⁺ +H), R_(f) =0.13 (methylenechloride:methanol:concentrated ammonia solution=80:20:1).

EXAMPLE 15

Analogously to Example 6 there is obtained from 100 mg (0.251 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]4-(2-chloro-5-pyridyl)-2-pyrimidineamine,dissolved in 1 ml of dimethylformamide, and 0.33 ml (2.5 mmol) of1-(2-aminoethyl)-piperazineN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-{2-(4-formylpiperazinyl)ethylamino}-5-pyridyl]-2-pyrimidineamine; MS(FAB): 520 (M⁺ +H), R_(f) =0.4(methylene chloride:methanol:concentrated ammonia solution=80:20:1).

EXAMPLE 16

0.58 ml of hydrogen peroxide (30%), 0.16 ml of 1-hexene, 11 mg of sodiumcarbonate and 2 ml of methanol are added to 50 mg (0.12 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-cyano-4-pyridyl)-2-pyrimidineamineand the reaction mixture is stirred for 14 h at RT. The product isisolated by filtration, washed with methanol/water (9:1) and dried togiveN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-carbamoyl-4-pyridyl)-2-pyrimidineamine;m.p. 224°-225°, FAB-MS: 408 (M⁺ +H), 290.

The starting material is obtained in the following manner:

Stage 16.1: 23.6 g (75 mmol) of3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate are added to asolution of 13.2 g (75 mmol) of3-dimethylamino-1-(4-pyridyl)-2-propen-1-one [described in EP-A-0 233461 ] in 500 ml of isobutanol. After the addition of 4 g (100 mmol) ofsodium hydroxide, the reaction mixture is stirred for 3 h at 110°. Thesuspension is concentrated under reduced pressure and the residue isdissolved in 500 ml of methylene chloride/tetrahydrofuran (1:1) andextracted with 300 ml of water. The organic phase is dried (Na₂ SO₄) andconcentrated using a rotovapor. Recrystallisation from diethylether/tetrahydrofuran givesN-[3-(1,1,2,2-tetrafluoro-ethoxy-phenyl]-4-(4-pyridyl)-2-pyrimidine-amine;R_(f) =0.9 (methylene chloride:methanol=9:1), FAB-MS:365 (M⁺ +H), m.p.191°-192°.

Stage 16.2: 500 mg (1.37 mmol)ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4(4-pyridyl)-2-pyrimidineamineare suspended in 10 ml of methylene chloride; 430 mg (1.37 mmol) ofm-chloroperbenzoic acid are added and the reaction mixture is stirredfor 4 h at RT. After extraction with water and 2N aqueous sodiumhydroxide solution, the organic phase is dried and concentrated using arotovapor. Chromatography (methylene chloride/methanol=19:1 to 9:1) andsubsequent crystallisation (methylene chloride/diethyl ether) giveN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(N-oxido-4-pyridyl)-2-pyrimidineaminein the form of lemon-yellow crystals; FAB-MS: 381 (M⁺ +H), m.p.191°-192°.

Stage 16.3: 100 mg (0.26 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(N-oxido-4-pyridyl)-2-pyrimidineamine,90 μl (0.72 mmol) or trimethylsiyl cyanide and 66 μl (0.72 mmol ofN,N-dimethyl-carbamoyl chloride are dissolved in 5 ml of acetonitrileand stirred at 60° for 14 h. Concentration under reduced pressure andrecrystalisation from tetrahydrofuran/diethyl ether giveN-[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]-4-(2-cyano-4-pyridyl)-2-pyrimidineamine;FAB-MS: 390 (M⁺ +H), R_(f) =0.7 (hexane:ethyl acetate=1:1).

EXAMPLE 17

30 mg (0.077 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-cyano-4-pyridyl)-2-pyrimidineamineare stirred for 2 hours at 60° in 5 ml of ethanol and 5 ml of 2N sodiumhydroxide solution. After acidfying with 4N hydrochloric acid, theproduct is isolated by filtration, washed with water and dried under HVat 50°.N-[3-1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-carboxy-4-pyridyl)-2-pyrimidineamineis obtained; m.p. 186°-187°, FAB-MS: 409 (M⁺ +H), 408 (M⁺), 365.

EXAMPLE 18

Analogously to Example 1 there is obtained from 320 mg (0.83 mmol) of3-dimethylamino-1-[1-(2-phthalimido-ethyl)-3-1H-indoyl]-2-propen-1-one,40 mg (1.0 mmol) of sodium hydroxide and 260 mg (0.826 mmol) of3-(1,1,2,2-tetrafluoroethoxy)-phenyl-guanidine nitrateN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[1-(2-phthalimido-ethyl)-3-1H-indolyl]-2-pyrimidineamine;m.p. 213°-215°, FAB-MS: 576 (M⁺ +H).

The starting material is obtained in the following manner:

Stage 18.1: 2.5 g (15.7 mmol) of 3-acetyl-1H-indole are dissolved in 100ml of dimethylformamide, and 0.41 g (15.7 mmol) of sodium hydride and4.0 g (16 mmol) of N-(2-bromo-ethyl)-phthalimide are added. The reactionmixture is stirred for 14 h at RT and for 3 h at 50°. 20 ml of water areadded and the product is isolated by filtration. After drying at 50°under HV,N-[2-(3-acetyl-1H-indol-1-yl)-ethyl]-1H-isoindole-1,3(2H)-dione isobtained; ¹ H-NMR (CDCl₃): 2.5 (3H,s), 4.1 (2H,t), 4.45 (2H,t), 7.2-7.9(8H,m), 8.35 (1H n).

Stage 18.2: 0.61 g (1.8 mmol) ofN-[2-(3-acetyl-1H-indol-1-yl)-ethyl]-1H-isoindole-1,3-(2H)-dione isstirred for 170 h in 10 ml of dimethylformamide diethylacetal. Afterconcentration using a rotovapor and chromatography (ethylacetate:acetone=9:1),3-dimethyl-amino-1-[1-(2-phthalimido-ethyl)-3-1H-indoly]-2-propen-1-oneis obtained; ¹ H-NMR (CDCl₃): 3.0 (6H, s), 4.1 (2H,t) 4.4 (2H,f), 5.6(1H,d), 7.2-7.9 (9H,m), 8.4 (1H, m).

EXAMPLE 19

Analogously to Example 1 there is obtained from 2.0 g (5 mmol) of3-dimethylamino-1-[1-(3-phthalimido-propyl)-3-1H-indolyl]-2-propen-1-one,0.28 g (7 mmol) of sodium hydroxide and 1.56 g (5 mmol) of3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate in 100 ml ofisobutanol, after 48 h under reflux,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[1-(3-phthalimido-propyl)-3-1H-indolyl]-2-pyrimidineamine;m.p 137°-138°, R_(f) =0.5 (hexane:diethyl ether=1:1).

The starting material is obtained in the following manner:

Stage 19.1:

Analogously to Stage 18.1 there is obtained from 5.0 g (31.4 mmol) of3-acetyl-1H-indole, 0.83 g (31.4 mmol) of sodium hydried and 6.4 g (31.4mmol) of N-(3-bromo-propyl)-phthalimideN-[3-acetyl-1H-indol-1-yl)-propyl]-1H-isoindole-1,3 (2H)-dione; R_(f)=0.87 (methylene chloride:methanol=9:1).

Stage 19.2

Analogously to Stage 18.2 there is obtained from 2.0 g (5.8 mmol) ofN-[3-(3-acetyl-1H-indol-1-yl)-propyl]-1H-isoindole-1,3(2H)-dione and 10ml of dimethylformamide diethylacetal3-dimethylamino-1-[1-(3-phthalimido-propyl)-3-1H-indolyl]-2-propen-1-one;R_(f) =0.4 (ethyl acetate:acetone=9:1).

EXAMPLE 20

In a manner analogous to that described above and by simple conversionreactions, known per se, of the products, the following compounds areprepared:

a)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-imidazolylethyl-amino)-4-pyridyl]-2-pyrimidineamine,

b )N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-acetamidoethylamino)-4-pyridyl]-2-pyrimidineamine,

c)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-propylamino-4-pyridyl)-2-pyrimidineamine,

d)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-amino-4-pyridyl)-2-pyrimidineamine,

e)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-hydrazino-4-pyridyl)-2-pyrimidineamine,

f)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-guanidylethylamino)-4-pyridyl]-2-pyrimidineamine,

g)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-{2-(methylamino-carbonylamino)ethyl}-4-pyridyl]-2-pyrimidineamine,

h)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-amidino-ethyl)-4-pyridyl]-2-pyrimidineamine,

i)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-glycylamido-ethyl-amino)-4-pyridyl]-2-pyrimidinea1310mine,

j)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[N-(3-amino-propyl)-3-1H-indolyl]-2-pyrimidineamine,

k)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[N-(2-amino-ethyl)-3-1H-indolyl]-2-pyrimidineamine,

1)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-nitro-phenyl)-2-pyrimidineamine,

m)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-aminocarbonyl-phenyl)-2-pyrimidineamine,

n)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[3-{N-(2-amino-ethyl)carbamoyl}-phenyl]-2-pyrimidineamine,

o)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[3-{N-(2-hydroxy-ethyl)-carbamoyl}-phenyl]-2-pyrimidineamine,

p)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-carboxy-phenyl)-2-pyrimidineamine,

q)N-(5-benzoylamino-phenyl)-4-[2-(2-amino-ethyl-amino)-4-pyridyl]-2-pyrimidineamine,

r)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-hydroxy-4-pyridyl)-2-pyrimidineamine,

s)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-methoxy-4-pyridyl)-2-pyrimidineamine,

t)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-{N-(2-amino-ethyl)carbamoyl}-4-pyridyl]-2-pyrimidineamine(see also Example 30),

u)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-{N-(2-hydroxy-ethyl)carbamoyl}-4-pyridyl]-2-pyrimidineamine(see also Example 28),

v)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-{N-(3-amino-propyl)carbamoyl}-4-pyridyl]-2-pyrimidineamine(see also Example 31) and

w)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-{N-(3-hydroxy-propyl)carbamoyl}-4-pyridyl]-2-pyrimidineamine(see also Example 29).

EXAMPLE 21

11.97 g (56.82 mmol)of3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one are suspended in114 ml of 2-propanol. 14.27 g (56.82 mmol) of3-(1,1,2,2-tetra-fluoro-ethoxy)-phenyl-guanidine nitrate (forpreparation see Stage 1.1) and 2.5 g (62.5 mmol) of sodium hydroxide areadded, and the reaction mixture is boiled under reflux for 17 h. Aftercooling to RT, the product is isolated by filtration, washed with2-propanol and water and dried at 50° under HV.N-[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidinneamineis obtained; FAB-MS: 399 (M⁺ +H), m.p. 202°-204°.

The starting material is obtained in the following manner:

Stage 21.1: 24.61 g (177.62 mmol) of 2-chloro-4-cyano-pyridine areplaced in 1.25 liters of diethyl ether under nitrogen, and 120 ml (22%in tetrahydrofuran, 353 mmol) of methylmagnesium chloride are added. Thered suspension is stirred for 40 h at RT, poured onto 1.25 liters ofice/water and 250 ml of 6N hydrochloric acid and stirred for 14 h at RT.Extraction with diethyl ether and methylene chloride, drying with MgSO4and concentration give 4-acetyl-2-chloro-pyridine; R_(f) =0.5 (methylenechloride:methanol=9:1).

Stage 21.2: 16.2 g (104.2 mmol) of 4-acetyl-2-chloro-pyridine arestirred for 1 h at 110° with 116 ml of dimethylformamide diethylacetal.After cooling to 0°, filtering and drying at 60° under HV,3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one is obtained; ¹H-NMR (dimethyl sulfoxide): 2.98 (3H,s), 3.2 (3H,s), 5.9 (1H,d), 7.8(3H.m), 8.5

EXAMPLE 22

2 g (5.0 mmol)ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamineare stirred for 44 h at 100° in 30 ml of 3-amino-1-propanol. Afterconcentration by evaporation and chromatography (methylenechloride:methanol:conc. ammonia solution=95:5:1),N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(3-hydroxy-propyl-amino)-4-pyridyl]-2-pyrimidineamineis obtained; m.p. 141°-145°, MS(FAB): 438 (M⁺ +H), R_(f) =0.28(methylene chloride:methanol:conc. ammonia solution=95:5:1).

EXAMPLE 23

Analogously to Example 22 there is obtained from 100 mg (0.25 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-4-pyridyl)-2-Pyrimidineamineand 1.5 ml of ethanolamineN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-hydroxy-ethyl-amino)-4-4-pyridyl]-2-pyrimidineamine;R_(f) =0.2 (methylene chloride:methanol:conc. ammonia solution=95:5:1),FAB-MS: 424 (M⁺ +H).

EXAMPLE 24

Analogously to Example 22 there is obtained from 100 mg (0.25 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamineand 1.5 ml of 3-methoxypropylamineN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2(3-methoxy-propyl-amino)-4-pyridyl]-2-pyrimidineamine;FAB-MS: 452 (M⁺ +H), m.p. 150°-153°.

EXAMPLE 25

In a manner analogous to that described above and by simple conversionreactions, known per se, of the products, the following compounds areprepared:

a)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-hydroxy-propyl-amino)-4-pyridyl]-2-pyrimidineamine,

b)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-carboxy-ethyl-amino)-4-pyridyl]-2-pyrimidineamine(see also Example 27),

c)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-carbamoyl-ethyl-amino)-4-pyridyl]-2-pyrimidineamine,

d)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-ethoxycarbonylethylamino)-4-pyridyl]-2-pyrimidineamine,

e)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-naphthyl]-2-pyrimidineamine(see also Example 34),

f)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[1-naphthyl]-2-pyrimidineamine(see also Example 38),

g)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2,4-dichloro-phenyl]-2-pyrimidineamine,

h)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2,5-dichloro-phenyl]-2-pyrimidineamine(see also Example 35),

i)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[3,4-dichloro-phenyl]-2-pyrimidineamine(see also Example 36),

j)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2,3,4-trichloro-phenyl]-2-pyrimidineamine(see also Example 37),

k)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-chloro-phenyl]-2-pyrimidineamine(see also Example 33),

l)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[3-chloro-phenyl]-2-pyrimidineamine,

m)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[9-anthracenyl]-2-pyrimidineamine,

n)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-fluorenyl]-2-pyrimidineamine,

o)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[3-(2-amino-ethyl-amino-sulfonyl)phenyl]-2-pyrimidineamine,

p)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[3-(1-piperazinyl-sulfonyl)-phenyl]-2-pyrimidineamine,

q)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[3-(2-amino-ethyl-amino)-phenyl]-2-pyrimidineamine,

r)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[3-(3-amino-propyl-amino)-phenyl]-2-pyrimidineamine

s)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-{2-(N-hydroxy-carbamoyl)-ethylamino}-4-pyridyl]-2-pyrimidineamine,

t)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-{3-(N-hydroxy-carbamoyl)-propylamino}-4-pyridyl]-2-pyrimidineamine,

u)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-dihydroxyphosphoryloxy-ethylamino)-4-pyridinyl]-2-pyrimidineamineand

v)N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(3-dihydroxyphosphoryloxy-propylamino)-4-pyridyl]-2-pyrimidineamine.

EXAMPLE 26

Analogously to Example 6 them is obtained from 100 mg (0.251 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamineand 100 mg (1.33 mmol) of glycine in 3 ml of1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), after extraction with citricacid and crystallisation from THF/diethyl ether,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(carboxymethyl-amino)-4-pyridyl]-2-pyrimidineamine;m.p. 116°-117°, FAB-MS: 438 (M⁺ +H).

EXAMPLE 27

Analogously to Example 6 there is obtained from 500 mg (1.25 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamineand 500 mg (5.6 mmol) of β-alanine in 15 ml of1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), after extraction with aqueouscitric acid and flash chromatography (methylenechloride:methanol:HCOOH=90:10:1),N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-carboxyethylamino)-4-pyridyl]-2-pyrimidineamine;m.p. 108°-110° , FAB-MS: 452 (M⁺ +H).

EXAMPLE 28

100 mg (0.2 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine,73 mg (0.38 mmol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimidehydrochloride and 44 mg (0.38 mmol) of N-hydroxysuccinimide aredissolved in 3 ml of dimethyflormamide and stirred for 2.5 h at RT. Thereaction mixture is then added dropwise at 0° over a period of 30minutes to a solution of 0.75 ml (12.3 mmol) of ethanolamine in 2 ml ofDMF. After stirring for 14 h at RT, the reaction mixture is poured into50 ml of ethyl acetate and extracted with aqueous sodium chloridesolution (30 ml) and pH 7 buffer (30 ml), and the organic phase is dried(sodium sulfate) and concentrated. Crystallisation from THF/diethylether givesN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-hydroxy-ethyl-aminocarbonyl)-4-pyridyl]-2-pyrimidineamine;m.p. 159°, FAB-MS: 452 (M⁺ +H).

EXAMPLE 29

Analogously to Example 28 there is obtained from 100 mg (0.2 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine, 73 mg (0.38 mmol) ofN-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride, 44 mg(0.38 mmol) of N-hydroxysuccmimide and 0.6 ml (8 mmol) of aminopropanolN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(3-hydroxy-propyl-aminocarbonyl)-4-pyridyl]-2-pyrimidineamine;m.p. 108°-110°, FAB-MS: 466 (M⁺ +H).

EXAMPLE 30

Analogously to Example 28 there is obtained from 100 mg (0.2 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-carboxy -4-pyridyl)-2-pyrimidineamine, 73 mg (0.38 mmol) ofN-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride, 44 mg(0.38 mmol) of N-hydroxysuccinimide and 0.9 ml of ethylenediamine, aftercrystallisation from isopropanol/ethanolic hydrochloric acid,N-[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]-4-[2-(2-amino-ethyl-aminocarbonyl)-4-pyridyl]-2-pyrimidineaminehydrochloride; m.p. 146-153°, FAB-MS: 451 (M⁺ +H).

EXAMPLE 31

Analogously to Example 28 there is obtained from 100 mg (0.2 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine,73 mg (0.38 mmol) of N-ethyl-'-(3-dimethylaminopropyl)-carbodiimidehydrochloride, 44 mg (0.38 mmol) of N-hydroxysuccinimide and 0.96 ml(12.9 mmol) of 1,3-diaminopropane, after crystallisation fromisopropanoy/ethanolic hydrochloric acid,N-[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]-4-[2-(3-amino-propyl-aminocarbonyl)-4-pyridyl]-2-pyrimidineaminehydrochloride; m.p. 149°-157°, FAB-MS: 465 (M⁺ +H).

EXAMPLE 32

Analogously to Example 1 there is obtained from 10.99 g (54.9 mmol) of3-dimethylamino-1-(3-cyano-phenyl)-2-propen-1-one, 13.79 g (54.9 mmol)of 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate and 2.42 g(60.4 mmol) of sodium hydroxideN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-cyano-phenyl)-2-pyrimidineamine;m.p. 180-182°, FAB-MS: 389 (M⁺ +H).

The starting material is obtained in the following manner:

Stage 32.1: Analogously to Stage 1.1 there is obtained from 9.70 g (66.8mmol) of 3-acetyl-benzonitrile and 74.44 ml (434.3 mmol) ofN,N-dimethylformamide diethylacetal3-dimethylamino-1-(3-cyano-phenyl)-2-propen-1-one; ¹ H-NMR (DMSO): 2.9(s,3H), 3.2 (s,3H), 5.9 (d, 1H), 7.6-8.3 (m,5H).

EXAMPLE 33

Analogously to Example 1 there is obtained from 200 mg (0.95 mmol) of3-dimethylamino-1-(2-chloro-phenyl)-2-propen-1-one, 240 mg (0.95 mmol)of3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate and 42 mg (1.05mmol) of sodium hydroxideN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-phenyl)-2-pyrimidineamine;m.p. 95°-101 °, FAB-MS: 398 (M⁺ +H).

The starting material is obtained in the following manner:

Stage 33.1

Analogously to Stage 1.1 there is obtained from 1.0 g (6.5 mmol) of2-chloroacetophenone and 7.2 ml (42.0 mmol) of N,N-dimethylformamidediethylacetal 3-dimethylamino-1-(2-chloro-phenyl)-2-propen-1-one; ¹H-NMR (DMSO): 2.9 (s, 3H), 3.1 (s,3H), 5.2 (d, 1H), 7.3-7.5 (m,5H).

EXAMPLE 34

Analogously to Example 1 there is obtained from 200 mg (0.89 mmol) of3-dimethylamino-1-(2-naphthyl)-2-propen-1-one, 223 mg (0.89 mmol) of3-(1,1,2,2-tetra-fluoro-ethoxy)-phenyl-guanidine nitrate and 39 mg (0.97mmol) of sodium hydroxideN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-naphthyl)-2-pyrimidineamine;m.p. 126°-128°, FAB-MS: 414 (M⁺ +H).

The starting material is obtained in the following manner:

Stage 34.1: Analogously to Stage 1.1 there is obtained from 1.0 g (5.9mmol) of 2-methyl naphthyl ketone and 6.5 ml (38.2 mmol) ofN,N-dimethylformamide diethylacetal3-dimethylamino-1-(2-naphthyl)-2-propen-1-one; ¹ H-NMR (DMSO): 3.0(s,3H), 3.2 (s,3H), 6.0 (d, 1H), 7.5-8.1 (m,7H), 8.5 (s, 1H).

EXAMPLE 35

Analogously to Example 1 there is obtained from 200 mg (0.82 mmol) of3-dimethylamino-1-(2,5-dichloro-phenyl)-2-propen-1-one, 206 mg (0.82mmol) of 3(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate and 22.5mg (0.9 mmol) of sodium hydroxideN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2,5-dichloro-phenyl)-2-pyrimidineamine;m.p. 123°-126°, FAB-MS: 432 (M⁺ +H).

The starting material is obtained in the following manner:

Stage 35.1: Analogously to Stage 1.1 there is obtained from 1.0 g (5.3mmol) of 2,5-dichloro-acetophenone and 5.9 ml (34.4 mmol) ofN,N-dimethylformamide diethylacetal3-dimethylamino-1-(2,5-dichloro-phenyl)-2-propen-1-one; ¹ H-NMR (DMSO):2.9 (s,3H), 3.3 (s,3H), 5.2 (d, 1H), 7.3-7.6 (m,4H).

EXAMPLE 36

Analogously to Example 1 there is obtained from 200 mg (0.82 mmol) of3-dimethylamino-1-(3,4-dichloro-phenyl)-2-propen-1-one, 206 mg (0.82mmol) of 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate and22.5 mg (0.9 mmol) of sodium hydroxideN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3,4-dichloro-phenyl)-2-pyrimidineamine;m.p. 121°-123°, FAB-MS: 432 (M⁺ +H).

The starting material is obtained in the following manner:

Stage 36.1: Analogously to Stage 1.1 there is obtained from 1.0 g (5.3mmol) of 3,4-dichloro-acetophenone and 5.9 ml (34.4 mmol) ofN,N-dimethylformamide diethylacetal3-dimethylamino-1-(3,4-dichloro-phenyl)-2-propen-1-one; ¹ H-NMR (DMSO):2.9 (s,3H), 3.2 (s,3H), 5.9 (d, 1H), 7.7-8.1 (m,4H).

EXAMPLE 37

Analogously to Example 1 there is obtained from 200 mg (0.89 mmol) of3-dimethylamino-1-(2,3,4-trichloro-phenyl)-2-propen-1-one, 224.8 mg(0.89 mmol) of 3(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrateand 39.4 mg (0.98 mmol) of sodium hydroxideN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2,3,4-trichloro-phenyl)-2-pyrimidineamine;m.p. 131°-133°, FAB-MS: 466 (M⁺ +H).

The starting material is obtained in the following manner:

Stage 37.1: Analogously to Stage 1.1 there is obtained from 1.0 g (4.5mmol) of 2,3,4-trichloroacetophenone and 7.2 ml (42.0 mmol) ofN,N-dimethylformamide diethyhcetal3-dimethylamino-1-(2,3,4-trichloro-phenyl)-2-propen-1-one; ¹ H-NMR(DMSO): 2.9 (s,3H), 3.3 (s,3H), 5.2 (d,1H), 7.2-7.7 (m,3H).

EXAMPLE 38

Analogously to Example 1 there is obtained from 200 mg (0.89 mmol) of3-dimethylamino-1-(1-naphthyl)-2-propen-1-one, 223 mg (0.89 mmol) of3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate and 39.1 mg(0.98 mmol) of sodium hydroxideN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(1-naphthyl)-2-pyrimidineamine;FAB-MS: 414 (M⁺ +H), 296, 205.

The starting material is obtained in the following manner:

Stage 38.1: Analogously to Stage 1.1 there is obtained from 1.0 g (5.88mmol) of 1-methyl naphthyl ketone and 6.5 ml (38.2 mmol) ofN,N-dimethylformamide diethylacetal3-dimethylamino-1-(1-naphthyl)-2-propen-1-one; R_(f) =0.19 (methylenechloride:methanol=98:2).

EXAMPLE 39

100 mg (0.26 mmol) ofN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-cyano-4-pyridyl)-2-pyrimidineamineand 1.28 ml (1.0M in THF, 1.28 mmol) of diisobutylaluminium hydride/THFsolution are stirred for 1 h at -20°. After the addition of 2 ml ofmethanol, the reaction mixture is heated to RT and the reaction productis isolated by filtration. After concentration under reduced pressureusing a rotovapor and chromatography [methylenechloride:methanol:ammonia(conc.)=95:5:]N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-aminomethyl-4-pyridyl)-2-pyrimidineamineis obtained; m.p. 64°-67°, FAB-MS: 394 (M⁺ +H).

EXAMPLE 40

Analogously to Example 1 there is obtained from 5.07 g (23.02 mmol) of3-dimethylamine-1-(3-nitro-phenyl)-2-propen-1-one, 5.78 g (23.02 mmol)of 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate and 1.0 g(25.32 mmol) of sodium hydroxideN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-nitro-phenyl)-2-pyrimidineamine;m.p. 158°-163°, FAB-MS: 409 (M⁺ +H).

The starting material is obtained in the following manner:

Stage 40.1: Analogously to Stage 1.1 there is obtained from 4.64 g(27.24 mmol) of 3-nitro-acetophenone and 18.05 ml (105.3 mmol) ofN,N-dimethylformamide diethylacetal3-dimethylamino-1-(3-nitro-phenyl)-2-propen-1-one; ¹ H-NMR (DMSO): 3.0(s,3H), 3.2 (s,3H), 5.9 (d, 1H), 7.8 (m,2H), 8.3 (m,2H), 8.6 (m,1H).

EXAMPLE 41

Tablets each comprising 20 mg of active ingredient, for example one ofthe compounds of formula I described in Examples 1-40, are prepared withthe following composition in customary manner:

    ______________________________________                                        Composition:                                                                  ______________________________________                                        active ingredient                                                                              20 mg                                                        wheat starch     60 mg                                                        lactose          50 mg                                                        colloidal silica  5 mg                                                        talc              9 mg                                                        magnesium stearate                                                                              1 mg                                                                         145 mg                                                       ______________________________________                                    

Preparation:

The active ingredient is mixed with a portion of the wheat starch, withthe lactose and with the colloidal silica, and the mixture is forcedthrough a sieve. A further portion of the wheat starch is made into apaste with 5 times the amount of water on a water bath, and the powdermixture is kneaded with the paste until a slightly plastic mass has beenformed.

The plastic mass is pressed through a sieve of approximately 3 mm meshsize and dried, and the resulting dry granules are forced through asieve again. The remainder of the wheat starch, the talc and themagnesium stearate are admixed and the mixture is compressed to formtablets each weighing 145 mg and having a breaking notch.

EXAMPLE 42

Capsules each comprising 10 mg of active ingredient, for example one ofthe compounds of formula I described in Examples 1-40, are prepared incustomary manner as follows:

    ______________________________________                                        Composition:                                                                  ______________________________________                                        active ingredient                                                                              2500 mg                                                      talc              200 mg                                                      colloidal silica  50 mg                                                       ______________________________________                                    

Preparation:

The active ingredient is intimately mixed with the talc and thecolloidal silica, and the mixture is forced through a sieve of 0.5 mmmesh size and introduced in 11-mg portions into hard gelatin capsules ofsuitable size.

What is claimed is:
 1. An N-phenyl-2-pyrimidineamine derivative offormula I ##STR9## wherein R₁ isa) naphthyl, b) fluorenyl, c)anthracenyl or d) a substituted cyclic radical, the cyclic radical beingbonded to a ring carbon atom in each case and being selected by fromphenyl, pyridyl, 1H-indolyl, pyrazinyl, thiazolyl, pyrimidinyl,pyridazinyl and imidazolyl, and the substituents of the above-mentionedphenyl radical being selected fromα) hydroxy, β) halogen, γ) nitro, δ)cyano, ε) unsubstituted or halogen-substituted lower alkoxy, ζ) aradical of formula II

    --C(═O)--(O).sub.m --R.sub.3                           (II)

wherein m is 0 or 1 and R₃ is hydrogen, benzyl, lower alkyl oramino-lower alkyl wherein the amino group is free, lower alkylated orlower alkoxylated,η) a radical of formula III

    --C(═O)--N(R.sub.4)R.sub.5                             (III)

wherein R₄ and R₅ are each independently of the other hydrogen orunsubstituted or amino- or hydroxy-substituted lower alkyl,θ) a radicalof formula IV

    --SO.sub.2 --N(R.sub.6)R.sub.7                             (IV)

wherein R₆ and R₇ are each independently of the other hydrogen, loweralkyl or amino-lower alkyl, or wherein R₆ and R₇ together form thebivalent radical --(CH₂)₂ --NH--(CH₂)₂ --, andι) a radical of formula V

    --N(R.sub.8)R.sub.9                                        (V)

wherein R₈ and R₉ are each independently of the other lower alkyl, orwherein R₈ is hydrogen and R₉ is amino or amino-cyclohexyl, or is loweralkyl that is substituted by imidazolyl, guanidyl, loweralkylamino-carbonylamino, amidino, di-lower alkylamino-cyclohexyl,piperazinyl, carboxy, lower alkoxycarbonyl, carbamoyl,N-hydroxy-carbamoyl, hydroxy, lower alkoxy, dihydroxyphosphoryloxy or byformylpiperazinyl, and the substituents of the other above-mentionedcyclic radicals pyridyl, 1H-indolyl, pyrazinyl, thiazolyl, pyrimidinyl,pyridazinyl and imidazolyl being selected froma) hydroxy, b) halogen, c)cyano, d) amino-lower alkyl, e) unsubstituted or halogen-substitutedlower alkoxy, f) phthalimido-substituted lower alkyl, g) a radical ofthe above-mentioned formulae II, III or IV and h) a radical of formulaVI

    --N(R.sub.10)R.sub.11                                      (VI)

wherein R₁₀ and R₁₁ are each independently of the other hydrogen orlower alkyl, or wherein R₁₀ is hydrogen and R₁₁ is amino oramino-cyclohexyl, or is lower alkyl substituted by amino, loweralkylamino, di-lower alkylamino, lower alkanoylamino, imidazolyl,guanidyl, lower alkylamino-carbonylamino, amidino, di-loweralkylamino-cyclohexyl, piperazinyl, formylpiperazinyl, carboxy, loweralkoxycarbonyl, carbamoyl, N-hydroxy-carbamoyl, hydroxy, lower alkoxy,dihydroxyphosphoryloxy or by glycylamido; and R₂ is nitro,fluorine-substituted lower alkoxy or a radical of formula VII

    --N(R.sub.12)--C(═X)--(Y).sub.n --R.sub.13             (VII)

wherein R₁₂ is hydrogen or lower alkyl, X is oxo, thio, imino, N-loweralkyl-imino, hydroximino or O-lower alkyl-hydroximino, Y is oxygen orthe group NH, n is 0 or 1, and R₁₃ isa) an unsubstituted aliphatichydrocarbon radical having 5 to 22 carbon atoms, b) phenyl or naphthyleach of which is unsubstituted or substituted by α) cyano, β) loweralkyl that is unsubstituted or substituted by hydroxy, amino or by4-methyl-piperazinyl, γ) trifluoromethyl, δ) hydroxy, ε) lower alkoxy,ζ) lower alkanoyloxy, η) halogen, θ) amino, ι) lower alkylamino, χ)di-lower alkylamino, λ) lower alkanoylamino, μ) benzoylamino, ν)carboxy, or ξ) lower alkoxycarbonyl, c) lower alkyl which is substitutedby a phenyl or naphthyl radical as defined in the preceding paragraphb), d) a 5- or 6-membered cycloalkyl radical, e) lower alkyl which issubstituted by a 5- or 6-membered cycloalkyl radical, f) a thienyl or2-, 3- or 4-pyridyl radical or g) lower alkyl substituted by a thienylor a 2-, 3- or 4-pyridyl radical,or a salt of such a compound having atleast one salt-forming group.
 2. A compound according to claim 1 offormula I, wherein the substituted cyclic radical R₁ is selected fromphenyl, pyridyl and 1H-indolyl, the phenyl substituents being selectedfroma) unsubstituted or fluorine-substituted lower alkoxy, b) halogen,c) nitro, d) a radical of formula II whereinm is 1 and R₃ is hydrogen,and e) a radical of formula III whereinR₄ is hydrogen and R₅ is hydrogenor amino- or hydroxy-substituted lower alkyl, and the substituents ofthe other above-mentioned cyclic radicals being selected from a)hydroxy, b) halogen, c) lower alkoxy, d) amino- orphthalimido-substituted lower alkyl, e) a radical of formula II whereinmis 1 and R₃ is hydrogen, f) a radical of formula III whereinR₄ ishydrogen and R₅ is hydrogen or amino- or hydroxy-substituted loweralkyl, and g) a radical of formula VI whereinR₁₀ is hydrogen and R₁₁ isamino or amino-cyclohexyl, or is lower alkyl substituted by amino,di-lower alkylamino, lower alkanoylamino, imidazolyl, guanidyl, loweralkylamino-carbonylamino, amidino, di-lower alkylamino-cyclohexyl,piperazinyl, formyl-piperazinyl or by glycylamido; and R₂ isfluorine-substituted lower alkoxy or a radical of formula VII whereinR₁₂ is hydrogen, X is oxo, n is 0 and R₁₃ is phenyl,or a salt of such acompound having at least one salt-forming group.
 3. A compound accordingto claim 1 of formula I, wherein R₁ is naphthyl, 9-anthracenyl,2-fluorenyl or a substituted cyclic radical selected from phenyl,pyridyl and 1H-indolyl, the phenyl substituents being selected froma)C₁₋₂ alkoxy, b) chlorine, c) trifluoromethoxy, d) a radical of formulaII whereinm is 1 and R₃ is hydrogen, from a radical of formula IIIwhereinR₄ is hydrogen and R₅ is hydrogen or C₂₋₃ alkyl substituted inthe ω-position by amino or by hydroxy, e) a radical of formula IVwhereinR₆ is hydrogen and R₇ is 2-amino-ethyl, or R₆ and R₇ togetherform the bivalent radical --(CH₂)₂ --NH--(CH₂)₂ --, and f) a radical offormula V whereinR₈ is hydrogen and R₉ is C₂₋₃ alkyl substituted in theω-position by amino,the pyridyl substituents being selected from a)hydroxy, b) chlorine, c) methoxy, d) a radical of formula II whereinm is1 and R₃ is hydrogen, e) a radical of formula III whereinR₄ is hydrogenand R₅ is hydrogen or C₂₋₃ alkyl substituted in the ω-position by aminoor by hydroxy, f) a radical of formula IV whereinR₆ is hydrogen and R₇is 2-amino-ethyl, or R₆ and R₇ together form the bivalent radical-(CH₂)₂--NH--(CH₂)₂ --, and g) a radical of formula VI whereinR₁₀ is hydrogenand R₁₁ is hydrogen, C₁₋₄ alkyl, amino, 4-amino-cyclohexyl or2-hydroxy-propyl, or is C₁₋₄ alkyl substituted in the co-position byamino, dimethylamino, acetylamino, imidazol-1-yl, guanidyl,methylamino-carbonylamino, amidino, 4-dimethylamino-cyclohexyl,piperazin-1-yl, 4-formyl-- piperazin-1-yl, carboxy, ethoxycarbonyl,carbamoyl, N-hydroxy-carbamoyl, hydroxy, methoxy, dihydroxyphosphoryloxyor by glycylamido, and the 1H-indolyl substituents being selected fromC₂₋₃ alkyl substituted in the ω-position by amino or by phthalimido; andR₂ is 1,1,2,2-tetrafluoro-ethoxy or a radical of formula VII wherein R₁₂is hydrogen, X is oxo, n is 0 and R₁₃ is phenyl,or a salt of such acompound having at least one salt-forming group.
 4. A compound accordingto claim 1 of formula I, wherein R₁ is a substituted cyclic radicalselected from phenyl, pyridyl and 1H-indolyl, the phenyl substituentsbeing selected froma) C₁₋₂ alkoxy, b) chlorine, c) trifluoromethoxy, d)a radical of formula II whereinm is 1 and R₃ is hydrogen, and e) aradical of formula III whereinR₄ is hydrogen and R₅ is hydrogen or C₂₋₋₃alkyl substituted in the ω-position by amino or by hydroxy,the pyridylsubstituents being selected from a) hydroxy, b) chlorine, c) methoxy, d)a radical of formula II whereinm is 1 and R₃ is hydrogen, e) a radicalof formula III whereinR₄ is hydrogen and R₅ is hydrogen or C₂₋₃ alkylsubstituted in the ω-position by amino or by hydroxy, and f) a radicalof formula VI whereinR₁₀ is hydrogen and R₁₁ is amino or4-amino-cyclohexyl, or is C₁₋₄ alkyl substituted in the ω-position byamino, dimethylamino, acetylamino, imidazolo-1-yl, guanidyl,methylamino-carbonylamino, amidino, 4-dimethylamino-cyclohexyl,piperazin-1-yl, 4-formyl-piperazin-1-yl or by glycylamido, and the1H-indolyl substituents being selected from C₂₋₃ alkyl substituted inthe ω-position by amino or by phthalimido; and R₂ is1,1,2,2-tetrafluoro-ethoxy or a radical of formula VII wherein R₁₂ ishydrogen, X is oxo, n is 0 and R₁₃ is phenyl,or a salt of such acompound having at least one salt-forming group.
 5. A compound accordingto claim 1 of formula I, wherein R₁ is naphthyl or a substituted cyclicradical selected from phenyl, pyridyl and 1H-indolyl, the phenylsubstituents being selected froma) C₁₋₂ alkoxy, b) chlorine, c)trifluoromethoxy, d) nitro, e) cyano, f) a radical of formula IIwhereinm is 1 and R₃ is hydrogen, and g) a radical of formula IIIwhereinR₄ is hydrogen and R₅ is hydrogen or C₂₋₃ alkyl substituted inthe ω-position by amino or by hydroxy,the pyridyl substituents being inthe ortho-position with respect to the pyridine nitrogen and beingselected from a) hydroxy, b) chlorine, c) methoxy, d) aminomethyl, e) aradical of formula II whereinm is 1 and R₃ is hydrogen, f) a radical offormula III whereinR₄ is hydrogen and R₅ is hydrogen or C₂₋₃ alkylsubstituted in the ω-position by amino or by hydroxy, and g) a radicalof formula VI whereinR₁₀ is hydrogen and R₁₁ is amino or4-amino-cyclohexyl, or is C₁₋₄ alkyl substituted in the ω-position byamino, dimethylamino, acetylamino, imidazol-1-yl, guanidyl,methylamino-carbonylamino, amidino, 4-dimethylamino-cyclohexyl,piperazin-1-yl, 4-formyl-piperazin-1-yl, glycylamido or by carboxy, andthe 1H-indolyl substituents being selected from C₂₋₃ alkyl substitutedin the ω-position by amino or by phthalimido; andR₂ is1,1,2,2-tetrafluoro-ethoxy or a radical of formula VII wherein R₁₂ ishydrogen, X is oxo, n is 0 and R₁₃ is phenyl,or a salt of such acompound having at least one salt-forming group.
 6. A compound offormual I according to claim 1 or a pharmaceutically acceptable salt ofsuch a compound having at least one salt-foming group, selectedfromN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3,4,5-trimethoxyphenyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-methoxy-phenyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(4-chloro-phenyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-ethoxy-phenyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-trifluoromethoxy-phenyl)-2-pyrimidineamine,N-3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-amino-ethyl-amino)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(3-dimethylamino-propyl-amino)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2,-tetrafluoro-ethoxy)phenyl]-4-[2-(4-amino-butylamino)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-{2-[2-(4-formyl-piperazinyl)-ethyl-amino]-4-pyridyl}-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-piperazinyl-ethyl-amino)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(cis-trans-4-amino-cyclohexylamino)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(cis-4-amino-cyclohexylamino)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-{(cis/trans-4-dimethylamino-cyclohexyl)-methylamino}-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-amino-ethyl-amino)-5-pyridyl]-2-pyridmidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(cis/trans-4-amino-cyclohexyl-amino)-5-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-{2-(4-formylpiperazinyl)-ethyl-amino}-5-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-carbamoyl-4-pyridyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[1-(2-phthalimido-ethyl)-3-1H-indolyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[1-(3-phthalimido-propyl)-3-1H-indolyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-imidazolylethyl-amino)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-acetamidoethylamino)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-propylamino-4-pyridyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-amino-4-pyridyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-hydrazino-4-pyridyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-guanidylethylamino-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-{2-(methylamino-carbonylamino)ethyl}-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-amidino-ethyl)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2,-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-glycylamido-ethyl-amino)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[N-(3-amino-propyl)-3-1H-indolyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[N-(2-amino-ethyl)-3-1H-indolyl]-2-pyrimidineamineN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-nitro-phenyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-aminocarbonyl-phenyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[3-{N-(2-amino-ethyl)carbamoyl}-phenyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[3-{N-(2-hydroxy-ethyl)-carbamoyl}-phenyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-carboxy-phenyl)-2-pyrimidineamine,N-(5-benzoylamino-phenyl)-4-[2-(2-amino-ethyl-amino)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-hydroxy-4-pyridyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-methoxy-4-pyridyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-{N-(2-amino-ethyl)carbamoyl}-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-{N-(2-hydroxy-ethyl)carbamoyl}-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-{N-(3-amino-propyl)carbamoyl}-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-{N-(3-hydroxy-propyl)carbamoyl}-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(3-hydroxy-propyl-amino)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-hydroxy-ethyl-amino)-4-pyrdyl-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(3-methoxy-propyl-amino)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-hydroxy-propyl-amino)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-carboxy-ethyl-amino)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-carbarmoyl-ethyl-amino)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-ethoxycarbonylethylamino)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-naphthyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[1-naphthyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2,4-dichloro-phenyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2,5-dichloro-phenyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[3,4-dichloro-phenyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2,3,4-trichloro-phenyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-chloro-phenyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[3-chloro-phenyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[9-anthracenyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-fluorenyl]-2-pyrimidineamineN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[3-(2-amino-ethyl-amino-sulfonyl)-phenyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[3-(1-piperazinyl-sulfonyl)-phenyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[3-(2-amino-ethyl-amino)-phenyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[3-(3-amino-propyl-amino)-phenyl]-2-pyrimidineaminN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-{2-(N-hydroxy-carbamoyl)-ethyl-amino}-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-{3-(N-hydroxy-carbamoyl)-propylamino}-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-dihydroxyphosphoryloxy-ethyl-amino)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(3-dihydroxyphosphoryloxy-propylamino)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2(carboxymethyl-amino)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-carboxyethylamino)-4-pyridyl]-2-pyridmidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-hydroxy-ethyl-aminocarbonyl)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(3-hydroxy-propyl-aminocarbonyl)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-amino-ethyl-aminocarbonyl)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(3-amino-propyl-aminocarbonyl)-4-pyridyl]-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-cyano-phenyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-phenyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-naphthyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2,5-dichloro-phenyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3,4-dichloro-phenyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2,3,4-trichloro-phenyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(1-naphthyl)-2-pyrimidineamine,N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-aminomethyl-4-pyridyl)-2-pyrimidineamineandN-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-nitro-phenyl)-2-pyrimidineamine,andfrom pharmaceutically acceptable salts of such compounds having at leastone salt-forming group.
 7. A pharmaceutical composition for thetreatment of tumours responsive to inhibition of protein kinase C,EGF-receptor-specific tyrosine protein kinase or p34^(cdc2)/cyclineB^(cdc13) kinase, in warm-blooded animals including humans,comprising a dose effective against tumours responsive to inhibition ofprotein kinase C, EGF-receptor-specific tyrosine protein kinase orp34^(cdc2) /cyclineB^(cdc13) kinase of a compound of formula I accordingto claim 1 or a pharmaceutically acceptable salt of such a compoundhaving at least one salt-forming group together with a pharmaceuticalcarrier.
 8. A method of treating a warm-blooded animal including ahuman, which comprises administering to such a warm-blooded animalsuffering from a tumour disease responsive to inhibition of proteinkinase C, EGF-receptor-specific tyrosine protein kinase or p34^(cdc2)/cyclineB^(cdc13) kinase a dose effective against tumours which areresponsive to inhibition of protein kinase C, EGF-receptor-specifictyrosine protein kinase or p34^(cdc2) cyclineB^(cdc13) kinase, of acompound of formula I according to claim 1 or of a pharmaceuticallyacceptable salt of such a compound having at least one salt-forminggroup.